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We would like to acknowledge the previous contributors to this review, including Nancy Tang and Elaine Wang.
Bronchiolitis is the most common lower respiratory tract infection in infants, occurring in a seasonal pattern, with highest incidence in the winter in temperate climates, and in the rainy season in warmer countries. Bronchiolitis is a common reason for attendance at and admission to hospital.
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of prophylactic interventions for bronchiolitis in high-risk children? What are the effects of measures to prevent transmission of bronchiolitis in hospital? What are the effects of treatments for children with bronchiolitis? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: bronchodilators (oral, inhaled salbutamol, inhaled adrenaline [epinephrine]), chest physiotherapy, corticosteroids, montelukast, nursing interventions (cohort segregation, hand washing, gowns, masks, gloves, and goggles), respiratory syncytial virus immunoglobulins, pooled immunoglobulins, or palivizumab (monoclonal antibody), ribavirin, or surfactants.
Bronchiolitis is a virally-induced acute bronchiolar inflammation that is associated with signs and symptoms of airway obstruction.
In high-risk children, prophylaxis with either respiratory syncytial virus immunoglobulin or the monoclonal antibody, palivizumab, reduces hospital admissions compared with placebo.
It seems that nursing interventions such as cohort segregation, hand washing and wearing gowns, masks, gloves and goggles successfully prevent spreading of the disease in hospital.
We do not know how effective most current interventions are in treating bronchiolitis.
Corticosteroids do not appear to be a useful treatment for bronchiolitis.
Bronchiolitis is a virally-induced acute bronchiolar inflammation that is associated with signs and symptoms of airway obstruction. Diagnosis: The diagnosis of bronchiolitis, as well as the assessment of its severity, is based on clinical findings (history and physical examination). Bronchiolitis is characterised by a cluster of clinical manifestations in children less than 2 years of age, beginning with an upper respiratory prodrome, followed by increased respiratory effort and wheezing. Suggestive findings include rhinorrhoea, cough, wheezing, tachypnoea, and increased respiratory distress manifested as grunting, nasal flaring, and chest indrawing. There is no good evidence supporting the value of diagnostic tests (chest radiographs, acute-phase reactants, viral tests) in infants with suspected bronchiolitis. RSV-test results rarely influence management decisions. Virologic tests, however, may be useful when cohorting of infants is feasible. Given these issues, it is not surprising to find wide variation in how bronchiolitis is diagnosed and treated in different settings.
Bronchiolitis is the most common lower respiratory tract infection in infants, occurring in a seasonal pattern, with highest incidence in the winter in temperate climates, and in the rainy season in warmer countries. Bronchiolitis is a common reason for attendance and admission to hospital. It accounted for around 3% (1.9 million) of emergency department visits in children below two years of age between 1992 and 2000 in the USA.The respiratory syncytial virus (RSV)-bronchiolitis hospitalisation rate in the USA infant population in 2000-2001 was 24.2 per 1000 births. In a retrospective cohort study carried out in the USA in 1989-1993, one third of RSV-associated hospitalisations were in infants less than three months old. Admission rates are even higher among infants and young children with bronchopulmonary dysplasia (BPD), congenital heart disease (CHD), prematurity, and other conditions such as chronic pulmonary diseases and immunodeficiency.
Respiratory syncytial virus is responsible for bronchiolitis in 70% of cases. This figure reaches 80-100% in the winter months. Reinfections are common and can occur throughout life. Other causal agents include human metapneumovirus, influenza, parainfluenza, and adenovirus.
Morbidity and mortality: Disease severity is related to the size of the infant, and to the proximity and frequency of contact with infective infants. It is estimated that 66 to 127 bronchiolitis-associated deaths occurred annually between 1979 and 1997 among US children aged under five years. Estimated annual RSV-attributed deaths in the UK were 8.4 per 100,000 in infants aged 1 to 12 months, and 0.9 per 100,000 population per year for children 1 to 4 years, between 1989 and 2000.Children at increased risk of morbidity and mortality include those with congenital heart disease, chronic lung disease, history of premature birth, hypoxia, immune deficiency, and age less than 6 weeks. Rates of admission to intensive care units are higher in those with one risk factor (17.7%) compared with those with no risk factors (3.2%). Rates of needing mechanical ventilation are also higher in those with one risk factor (13.1%) compared with those with no risk factor (1.5%). The risk of death within 2 weeks is higher for children with congenital heart disease (3.4%) or chronic lung disease (3.5%) compared with other groups combined (0.1%). The percentage of these children needing oxygen supplementation is also high (range 63-80%). Long-term prognosis: Studies on the long-term prognosis of bronchiolitis — in particular regarding its association with asthma, allergic sensitisation, and atopy — have not produced clear answers. Possible confounding factors include variation in illness severity, smoke exposure, and being in overcrowded environments.
To decrease morbidity and mortality, shorten hospital stay, and prevent transmission of infection, with minimal adverse effects.
Mortality; rates of hospital admission; duration of hospital stay; rate of intubation or admission to intensive care units; clinical scores (clinical scores are subjective, unvalidated measures that are based on judgements made by the clinician; two clinical scores are often used: RDAI [Respiratory Distress Assessment Instrument], which assigns a score for wheezing between 0 and 8 points and a score for retraction between 0 and 9 points, depending on the location and severity of these two signs, with 0 indicating the least severe; and RACS [Respiratory Assessment Change Score], which assesses the changes in RDAI plus the change in respiratory rate over time); rates of clinical and serological infection; and adverse effects of treatment. Oxygen saturation is a proxy outcome and is reported here, although the clinical significance and sensitivity of this outcome are unclear.
BMJ Clinical Evidence search October 2006. The following databases were used to identify studies for this review: Medline 1966 to October 2006, Embase 1980 to October 2006, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2006, Issue 4. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language containing more than 20 individuals of whom more than 80% were followed up. We included open label RCTs and there was no minimum length of follow-up required to include studies. We did a search for observational studies on nursing interventions for the prevention of transmission in hospital. We also searched for cohort studies on specific harms of named interventions and for information about prevention. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
MORTALITY Respiratory syncytial virus immunoglobulin or palivizumab (monoclonal antibody) compared with placebo or no prophylaxis: Prophylactic respiratory syncytial virus immunoglobulin or palivizumab (monoclonal antibody) given monthly (treament duration varied between 4-6 months) seems to be no more effective than placebo or no prophylaxis at reducing mortality in children with bronchopulmonary dysplasia or congenital heart disease ( moderate-quality evidence ). SYMPTOM IMPROVEMENT Respiratory syncytial virus immunoglobulin or palivizumab (monoclonal antibody) compared with placebo/no prophylaxis: Prophylactic respiratory syncytial virus immunoglobulin or palivizumab (monoclonal antibody) given monthly (treament duration varied between 4-6 months) seems to be more effective than placebo or no prophylaxis at reducing the proportion of children admitted to hospital, in children with bronchopulmonary dysplasia or congenital heart disease. We don't know whether prophylactic respiratory syncytial virus immunoglobulin or palivizumab (monoclonal antibody) is more effective than placebo or no prophylaxis at reducing the proportion of children admitted to intensive care units or receiving mechanical ventilation, in children with bronchopulmonary dysplasia or congenital heart disease (moderate-quality evidence).
We found one systematic review (search date 1999, 4 RCTs, 2598 high risk children)and one subsequent RCT comparing monthly respiratory syncytial virus immunoglobulin (RSV Ig) or palivizumab (monoclonal antibody) versus placebo or no prophylaxis. The review included RCTs in premature infants, children with bronchopulmonary dysplasia, or congenital heart disease. Three of the RCTs included in the review used intravenous RSV Ig and one used intramuscular palivizumab. Treatment duration varied between 4 and 6 months. Two of the RCTs using RSV Ig were open label and both used no prophylaxis as the control intervention. The systematic review found that, compared with placebo or no prophylaxis, RSV Ig or palivizumab reduced admission to hospital (95/1535 [6%] with RSV Ig or palivizumab v 138/1063 [13%] with placebo or no prophylaxis; OR 0.48, 95% CI 0.37 to 0.64) and to the intensive care unit (ICU) (27/1535 [2%] with RSV Ig or palivizumab v 43/1063 [4%] with placebo or no prophylaxis; OR 0.47, 95% CI 0.29 to 0.77). It found no significant difference in mechanical ventilation (16/1535 [1%] with RSV Ig or palivizumab v 14/1063 [1%] with placebo or no prophylaxis; OR 0.99, 95% CI 0.48 to 2.07) or in mortality (25/1535 [1.6%] with RSV Ig or palivizumab v 20/1063 [1.9%] with placebo or no prophylaxis; OR 1.15, 95% CI 0.63 to 2.11). The duration of follow up varied across RCTs in the systematic review from 150 days up to 17 months.
The subsequent RCT (1287 children and infants aged less than 24 months with haemodynamically significant congenital heart disease) compared palivizumab (15 mg/kg/month for 5 months) versus placebo during four RSV seasons. It found that palivizumab significantly reduced admissions to hospital compared with placebo (34/639 [5%] with palivizumab v 63/648 [10%] with placebo; RR 0.55, 95% CI 0.33 to 0.77). There was no significant difference in ICU admission or mechanical ventilation rates (ICU admissions: 13/639 [2%] with palivizumab v 24/648 [4%] with placebo; RR 0.54, no CI reported, P = 0.09; mechanical ventilation days/100 children: 6.5 with palivizumab v 54.7 with placebo; RR 0.12, no CI reported, P = 0.22). However, the study was not powered to detect a significant difference in these outcomes.
The subsequent RCT found no significant difference between palivizumab and placebo in overall adverse effects thought to be treatment related (46/639 [7.2%] with palivizumab v 45/648 [6.9%] with placebo; P = 0.91). Fever, injection site reactions, and severe cyanosis were slightly higher with palivizumab than with placebo (fever: 27% with palivizumab v 24% with placebo; injection site reactions: 3% v 2%; severe cyanosis: 4% v 2%; P values not reported). None of these adverse effects led to permanent treatment discontinuation. See also harms of immunoglobulins in question on treating brochiolitis.
Premature infants included in the RCTs were children under 6 months old, with gestational age at birth of less than either 32 or 35 weeks. Children with bronchopulmonary dysplasia were under 2 years old and were still receiving treatment for this disorder. Planned subgroup analysis in the review found that prophylaxis significantly reduced hospital admission in children whose only risk factor was prematurity (991 children; OR 0.27, 95% CI 0.15 to 0.49), and in children with bronchopulmonary dysplasia alone (1148 children; OR 0.54, 95% CI 0.37 to 0.80), but not in children with cardiac comorbidity alone (471 children; OR 0.64, 95% CI 0.37 to 1.10). However, the review might have lacked power to detect any differences in the children with cardiac disease. A cost-effectiveness analysis suggests that the clinical effect of palivizumab, when used in all children who meet the licensed indication for it, is small, and its benefits are likely to be more clinically relevant in children at the highest risk.
No new evidence
NOSOCOMIAL TRANSMISSION Nursing interventions (cohort segregation, hand washing, gowns, masks, gloves, and goggles) compared with no precautions or each other: Combined nursing interventions (including cohort segregation, gowns, hand washing, and gloves) may be more effective than individual interventions and no precautions at reducing nosocomial transmission in children ( very low-quality evidence ).
We found no systematic review and no RCTs examining effects of cohort segregation, hand washing, gowns, masks, gloves, or goggles, used either singly or in combination, on nosocomial transmission of bronchiolitis in children. We found one non-randomised trial (which also included a before–after study) and eight observational studies (see table 1 ). The non-randomised trial (128 children at risk of severe nosocomial infection) compared rates of infection in wards using different nursing policies. It found that a combination of cohort segregation, gowns, and gloves significantly reduced nosocomial transmission compared with all other policies (cohort segregation alone, gown and gloves alone, no special precautions) taken together. Gown and gloves alone or cohort nursing alone did not significantly reduce nosocomial transmission (P value not reported). However, the control interventions were not constant throughout the trial, the results were based on an interim analysis, and the definition of “at risk” children was not clearly stated. The before–after portion of the trial (128 children at risk of severe nosocomial infection; 23 in the before sample and 105 in the after sample) also found that nosocomial transmission was reduced after the implementation of a combination of cohort segregation, gowns, and gloves (significance assessment not performed). Six other observational studies found that a variety of nursing interventions reduced transmission rates. Two observational studies found no significant difference in transmission between interventions. The observational studies did not adjust results for variations in baseline incidence (see table 1 ).
Potential risks associated with cohort segregation include misdiagnosing respiratory syncytial virus infection, and putting non-infected people at risk by subsequent placement into the wrong cohort.
Dermatitis is a potential adverse effect of repeated hand washing with some products, affecting care providers.
No harms reported.
Hand washing is a well-established technique for reducing cross-infection in other contexts, and so RCTs may be difficult to justify ethically.
No new evidence
SYMPTOM IMPROVEMENT Bronchodilators compared with placebo or other bronchodilators: Inhaled brochodilators may be more effective than placebo at improving oxygen saturation (the clinical significance of which is inclear) in the outpatient setting. We don't know whether inhaled bronchodilators are more effective than placebo at improving clinical scores. Inhaled brochodilators may be no more effective than placebo at reducing the proportion of children admitted to hospital or in reducing the duration of hospital stay ( very low-quality evidence ).
We found three systematic reviews (search dates 1995 , 2006, 2003) and two additional RCTs. All of the RCTs identified by the first review were also identified by the second later review. However, the first review included RCTs of inhaled bronchodilators only, whereas the second review included inhaled, injected or oral bronchodilators, and both reviews performed different meta-analyses. Therefore we report results of both reviews here.
The first review evaluated inhaled salbutamol or fenoterol in children treated both in outpatient clinics and as inpatients. Participants, treatments, and outcomes varied considerably among the inpatient trials, precluding meta-analysis. A meta analysis of outpatient trials found that inhaled salbutamol significantly improved oxygen saturation, but that the improvement was not sufficiently large to be of clinical relevance (see table 2 ).The second review evaluated a range of bronchodilators other than adrenaline (including salbutamol, metaproterenol, fenoterol, ipratropium bromide, and aminophylline), in children in outpatient clinics or in the emergency department, and after admission to hospital.It included RCTs of bronchodilators (inhaled, injected or oral) in the meta-analysis, however, most identified studies involved inhaled bronchodilators. It carried out a subgroup analysis of inhaled bronchodilators for the outcome of hospital admission. It found that bronchodilators (inhaled or injected or oral) significantly improved overall mean clinical score compared with placebo. However, it found no significant difference between groups in the proportion of children demonstrating an improvement in their clinical score or in duration of hospital stay (see table 2 ). It also found no significant difference in hospital admission rates between the bronchodilators (inhaled) and placebo (see table 2 ).
The third review compared adrenaline versus placebo or versus salbutamol in inpatients and outpatients aged less than 2 years old. It included RCTs of treatments administered by any route. However, all but one of the identified RCTs assessed inhaled treatments. The review found different results for clinical scores and oxygen saturation at different times after treatment, and between subgroups of inpatients and outpatients (see table 2 ) . It found no significant difference between inhaled adrenaline and placebo or inhaled adrenaline and salbutamol in hospital admissions or duration of hospital stay (see table 2 ). The large number of comparisons examined may have have affected the validity of statistical assessments, and results should therefore be intrepreted with caution (see comment).
The first additional RCT compared nebulised salbutamol, nebulised racemic adrenaline [epinephrine] and saline placebo given at 0 and 30 minutes. A third dose was given at 60 minutes to children whose RDAI (Respiratory Distress Assessment Instrument) scores were above 8, or whose oxygen saturation was less than 90%. There were no significant differences among treatments in the frequency of the composite outcome of admission to hospital or discharge with home oxygen (see table 2 ).The second additional RCT compared nebulised racemic epinephrine with nebulised salbutamol. Racemic epinephrine resulted in a significant improvement in RDAI scores at day 2, but this was not considered to be clinically significant by the authors. There were no significant difference between the treatments regarding length of hospital stay (see table 2 ).
The second review reported tachycardia, increased blood pressure, decreased oxygen saturation, flushing, hyperactivity, prolonged cough, and tremor after use of bronchodilators. The review did not report the frequency of adverse effects. The first and third reviews gave no information on adverse effects. The first additional RCT reported that two patients who received salbutamol had a heartbeat above 200 beats per minute for more than 30 minutes. They both self-resolved after treatment was stopped.The second additional RCT found no significant difference between racemic epinephrine and salbutamol in vomiting (6/31 [19%] with epinepherine v 8/31 [26%] with salbutamol ), tremor (6/31 [19%] with epinepherine v 3/31 [10%] with salbutamol) and pallor (6/31 [19%] with epinepherine v 2/31 [6%] with salbutamol) during treatment (reported as not significant, P value not reported). One week after discharge from hospital, there continued to be no significant difference between groups in the rates of these adverse effects.
Only two of three systematic reviews pooled the clinical scores across trials. Although they found a statistically significant improvement in clinical scores (but not in rates of admission or length of hospital stay), the clinical meaning of this finding is uncertain. Discrepancies in primary studies included differences in study populations — such as inclusion of sedated children, short duration of follow-up, and validity of clinical scores. The systematic reviews performed multiple comparisons — which increases the chance of spurious statistical associations for some results. The evidence presented in the systematic reviews is difficult to interpret, because some of the RCTs did not exclude children with a history of wheezing, who may have asthma — a condition likely to respond to bronchodilators. In the third systematic review, separate analyses of inpatients and outpatients were not conducted for non-significant findings.
SYMPTOM IMPROVEMENT Compared with no corticosteroids: Systemic or inhaled corticosteroids may be no more effective than placebo, no treatment or usual care at reducing the proportion of children admitted to hospital, reducing the duration of hospital stay, the duration of mechanical ventilation, or improving clinical scores at day 3 ( very low-quality evidence ).
We found three systematic reviews and five subsequent RCTs. The first review (search date 2003, 13 RCTs, 1190 inpatient or ambulatory children) compared systemic corticosteroids (intramuscular, intravenous, or oral) versus control (mainly placebo — except in two studies that used quinine or mannitol). The review found no significant difference between corticosteroids and no corticosteroids in the duration of hospital stay (7 RCTs, 472 children; WMD –0.38 days, 95% CI –0.81 days to +0.05 days), clinical scores at day 3 (8 RCTs, 309 children; SMD –0.20, 95% CI –0.73 to +0.32), or in hospital admission rates (3 RCTs, 156 children; OR 1.05, 95% CI 0.23 to 4.87). It also found no significant difference in readmission rates between treatment groups (6 RCTs; reported as not significant; meta-analytical result not presented). The second review (search date 2002) included six RCTs that compared inhaled corticosteroids (a route of administration not addressed in the first review ) versus control (placebo, no treatment, or treatment as usual). This review did not conduct a meta-analysis, because of excessive heterogeneity among the trials (see comment below). Neither of the two RCTs that assessed duration of hospital stay in children treated with inhaled medication found differences between treatments. Three RCTs assessed hospital readmissions; two found no significant difference, and the third reported more readmissions with budesonide (absolute figures not reported). There was no consistent evidence of benefit for any other outcome. The third review (search date 2003) investigated the role of corticosteroids in the management of critically ill children with bronchiolitis, and included 3 RCTs (137 children) comparing corticosteroids (oral or intravenous) versus placebo (saline or unspecified). Only one of these RCTs was included in the first review. The systematic review found no significant difference between corticosteroids and placebo in duration of hospitalisation (2 RCTs, 96 children; WMD –2.44 days, 95% CI –9.30 days to +4.42 days) or in duration of mechanical ventilation (3 RCTs, 137 children; WMD –0.62 days, 95% CI –2.78 days to +1.53 days). The five subsequent RCTs evaluated various corticosteroids, the routes of administration, and co-interventions compared with no corticosteroids (see table 3 ). Three of these RCTs found no significant benefits from corticosteroids in children with bronchiolitis, and two found differences in clinical scores or in hospital stay. However, the RCTs that found differences conducted multiple simultaneous comparisons without making adjustments to the P value required for significance, therefore increasing the likelihood that these differences resulted by chance. It is doubtful whether these differences would be clinically meaningful (see table 3 ).
Although most of the studies included in the systematic reviews did not report on adverse effects, those that did found tremors (2 trials found 2 corticosteroid-treated infants and young children who were receiving concurrent nebulised salbutamol), and occult blood in faeces (1 trial found it in 2 dexamethasone-treated infants and in 1 placebo-treated infant). The acute adverse effects of oral corticosteroids are well documented, and include hyperglycaemia and immunosuppression. See harms of corticosteroids in asthma and other wheezing disorders of childhood.
The evidence presented in the systematic reviews is difficult to interpret because some of the RCTs did not exclude children with a history of wheezing, who may have asthma — a condition likely to respond to corticosteroids. The clinical scales used in the RCTs included oxygen saturation, but the clinical relevance of changes in this parameter are unclear. Even if the results are accepted at face value, the clinical significance of an effect size is unclear. We found inadequate evidence to evaluate the effects of systemic compared with inhaled corticosteroids. The open label RCT on the long-term effects of acute corticosteroids compared two different regimens of inhaled budesonide in inpatient children, and had several problems that further compromised its validity. Diagnosis of asthma was based only on a telephone survey — the children were not assessed to establish whether they had received additional interventions or exposures that could explain the results. The authors of the second review concluded that there was inconclusive evidence that systemic corticosteroid treatment (including inhaled corticosteroids) offered a benefit in terms of rates and duration of hospital stay, and that this kind of treatment does not seem to give an overall benefit, even when examining surrogate outcomes such as clinical scores.
MORTALITY Ribavirin compared with placebo or no ribavirin: Ribavirin seems to be no more effective than placebo at reducing mortality in children and infants admitted to hospital with respiratory syncytial virus bronchiolitis ( moderate-quality evidence ). SYMPTOM IMPROVEMENT Ribavirin compared with placebo or no ribavirin: Ribavirin may be more effective than placebo at reducing the duration of ventilation in children and infants admitted to hospital with respiratory syncytial virus bronchiolitis, but not in reducing the proportion of children with respiratory deterioration or in reducing the duration of hospital stay. Ribavirin may be no more effective than placebo at reducing the duration of oxygen supplementation or duration of hospital stay during the acute episode in inpatient infants who received ribavirin or placebo within 12 hours of admission, or in reducing admission rates for recurrent lower respiratory illness or use of bronchodilators at 1 year follow up. Nebulised ribavirin may be no more effective than no ribavirin at decreasing the frequency of recurrent wheezing illness over 1 years follow up in previously healthy infants less than 180 days old and admitted to hospital because of confirmed severe respiratory syncytial virus bronchiolitis ( low-quality evidence ).
We found one systematic review and two subsequent RCTs. The review (search date 2004, 12 small RCTs) found that, in children and infants admitted to hospital with respiratory syncytial virus bronchiolitis, ribavirin (tribavirin) did not significantly reduce mortality, respiratory deterioration, or duration of hospital stay compared with placebo (mortality: 3 RCTs, 158 children; 5/86 [6%] with ribavirin v 7/72 [10%] with placebo; RR 0.56, 95% CI 0.17 to 1.84; respiratory deterioration: 3 RCTs, 116 children; 4/56 [7%] with ribavirin v 11/60 [18%] with placebo; RR 0.38, 95% CI 0.13 to 1.11; duration of hospital stay: 3 RCTs, 104 children; WMD with ribavirin v placebo –1.9 days, 95% CI –4.6 days to +0.9 days). The high mortality in both groups may have been because of severe disease at baseline. The review found that ribavirin significantly reduced the duration of ventilation compared with placebo (3 RCTs, 104 children; WMD with ribavirin v placebo –1.8, 95% CI –3.4 to –0.2). However, this difference became non-significant if the one study using water as a placebo rather than saline was removed (2 RCTs, 78 children; WMD with ribavirin v placebo +1.08 days, 95% CI –2.83 days to +0.67 days). The first subsequent RCT (40 inpatient infants who received ribavirin or placebo within 12 hours of admission) found no significant difference in outcomes measured during the acute episode, such as the duration of oxygen supplementation or duration of hospital stay (duration of oxygen supplementation: 2.72 days with ribavirin v 1.92 days with placebo; mean difference +0.80 days, 95% CI –0.73 days to +2.32 days; duration of hospital stay: 4.94 days with ribavirin v 3.36 days with placebo; mean difference +1.58 days, 95% CI –0.18 days to +3.35 days). The RCT also followed the infants for 1 year after the initial episode. It found no significant difference in admission rates for recurrent lower respiratory illness, or in use of bronchodilators (admission for recurrent lower respiratory tract infection: 2/16 [13%] with ribavirin v 3/19 [16%] with placebo; RR 0.79, 95% CI 0.15 to 4.17; use of bronchodilators: 5/16 [31%] with ribavirin v 8/19 [42%] with placebo; RR 0.74, 95% CI 0.30 to 1.82). However, the study might have lacked power to rule out a clinically important difference. A second, open label RCT (45 previously healthy infants less than 180 days old and admitted to hospital because of confirmed severe respiratory syncytial virus bronchiolitis) compared nebulised ribavirin (60 mg/mL over 3 x 2-hour periods for a total of 6 g/100 mL every 24 hours for 3 days) versus no ribavirin. It found no significant difference in the frequency of recurrent wheezing illness over 1 year of follow-up (15/24 [63%] with ribavirin v 17/21 [81%] with placebo; RR 0.78, 95% CI 0.53 to 1.12).
We found no results from prospective studies. The systematic review and RCTs did not report on harms. We found case reports of headaches and contact lens dysfunction in carers. Ribavirin has been reported to be associated with acute bronchospasm in treated children. The standard aerosol is sticky, and clogging of ventilatory equipment has been reported.
The RCTs assessing the effectiveness of ribavirin were small, and might have lacked the power to detect clinically important differences. We found one small prospective study comparing pulmonary function tests in 54 children previously randomised to inpatient treatment with ribavirin or placebo. It found no evidence of long-term differences in outcome, although the study was not sufficiently powered to rule out a clinically important difference.
No new evidence
SYMPTOM IMPROVEMENT Respiratory syncytial virus immunoglobulin, pooled immunoglobulins, or palivizumab (monoclonal antibody) compared with placebo: Respiratory syncytial virus immunoglobulin (RSV Ig) may be no more effective than albumin placebo in reducing the duration of hospital stay in high-risk and non-high-risk children. Palivizumab may be no more effective than placebo at reducing duration of hospital stay, duration of ventilation, or duration of supplemental oxygen treatment, in children admitted to hospital with bronchiolitis. Pooled immunoglobulins may be no more effective than placebo at improving outcomes (not specified) in children admitted to hospital with bronchiolitis ( very low-quality evidence ).
We found no systematic review, but found five RCTs (4 using albumin solution as placebo control, 1 using 0.9% sodium chloride, 335 children in total). Two RCTs used pooled immunoglobulins, two RCTs used respiratory syncytial virus immunoglobulin (RSV Ig), and one RCT used palivizumab (synthetic monoclonal antibody). Neither of the RCTs using RSV Ig found evidence that RSV Ig shortened the duration of hospital stay compared with albumin placebo (in high-risk children: mean duration of hospital stay 8.41 days with RSV Ig v 8.89 days with placebo; P greater than 0.05; in non-high-risk children:mean stay 4.58 days with RSV Ig v 5.52 days with placebo ; P greater than 0.05; CI values not reported). The third RCT (35 children) found no evidence that palivizumab reduced duration of hospital stay, duration of ventilation, or duration of supplemental oxygen treatment compared with saline placebo (mean duration of hospital stay: 14.5 days with palivizumab v 11.5 days with placebo; P = 0.25; mean duration of ventilation: 8.8 days with palivizumab v 6.2 days with placebo; P = 0.45; mean duration of treatment with supplemental oxygen: 12.3 days with palivizumab v 9.5 days with placebo; P = 0.47). Neither of the remaining RCTs found any evidence that pooled immunoglobulins improved outcome in children with bronchiolitis.
The RCTs found that RSV Ig was associated with elevated liver enzymes and anoxic spells (frequency not reported). One open label RCT (249 children) of prophylactic RSV Ig found that adverse effects occurred in about 3% of treated children. The RCT and a subsequent analysis of the data found that effects included increased respiratory rate, mild fluid overload during the first infusion, urticarial reaction at the infusion site, mild decreases in oxygen saturation, and fever (no frequencies reported).
Four RCTs used albumin as placebo control. The effects of albumin in bronchiolitis are not known.
No new evidence
SYMPTOM IMPROVEMENT Oral bronchodilators compared with placebo: Oral salbutamol seems to be no more effective than placebo at shortening the time to resolution of illness or in reducing in the frequency of admission to hospital in infants with a clinical diagnosis of bronchiolitis ( moderate-quality evidence ).
We found one systematic review (search date 2006 ), and one additional RCT. The systematic review examined the effects of a range of bronchodilators (salbutamol, metaproterenol, fenoterol, ipratropium bromide, and aminophylline), either inhaled or injected or oral. It did not report a subgroup analysis based on the route of administration for any outcome except for hospital admission. Most of the identified studies involved inhaled bronchodilators (see benefits of bronchodilators [inhaled]). The review found no significant difference in hospital admission rates between salbutamol and placebo (1 RCT, 37 children, OR 0.32, 95% CI 0.03 to 3.21).The additional RCT (129 infants with a clinical diagnosis of bronchiolitis, discharged directly home after an emergency department visit) compared oral salbutamol (0.1 mg/kg/dose) versus oral placebo given three times daily for a maximum of 7 days or until complete resolution of bronchiolitis symptoms. The RCT found no significant difference in the time to resolution of illness or in the frequency of admission to hospital (mean time to resolution of illness: 8.9 days with salbutamol v 8.4 days with placebo; P = 0.5; frequency of admission: 4/64 [6%] with salbutamol v 5/65 [8%] with placebo; RR 0.81, 95% CI 0.20 to 2.90).
No new evidence
SYMPTOM IMPROVEMENT Compared with no chest physiotherapy: Chest physiotherapy may be no more effective than no chest physiotherapy at improving clinical scores (measured by heart rate, respiratory rate, hyperinflation, use of accessory muscles, recession, rhinitis, wheeze, cough, crepitations, and rhonchi) or at reducing length of hospital stay in hospitalised children with a clinical diagnosis of bronchiolitis not on mechanical ventilation ( very low-quality evidence ).
We found one systematic review (search date 2004, 3 RCTs, 172 hospitalised children with a clinical diagnosis of bronchiolitis who were not on mechanical ventilation, aged 0-24 months).The included trials compared different types of chest physiotherapy (hand chest percussion, postural drainage, cough induction, vibration, nasopharyngeal aspiration) versus standard care (not defined) without chest physiotherapy. The review did not perform a meta-analysis; none of the RCTs found that chest physiotherapy significantly improved clinical scores or reduced length of hospital stay compared with no physiotherapy. The first RCT identified by the review (90 children) found no significant difference in length of hospital stay (median length of stay: 4 days with chest physiotherapy v 4 days without chest physiotherapy; reported as non significant, P value not reported). The second RCT identified by the review (50 children) found no significant improvement in clinical score with chest physiotherapy during the five days of the trial compared with no chest physiotherapy (absolute results presented graphically; reported as not significant, P value not reported). The clinical score was calculated by assigning a score of zero to three for each of 10 clinical signs (heart rate, respiratory rate, hyperinflation, use of accessory muscles, recession, rhinitis, wheeze, cough, crepitations, and rhonchi) to give a total severity clinical score of a maximum of 30 points. The RCT also found no significant difference between chest physiotherapy and no physiotherapy in length of hospital stay (mean 6.7 days with chest physiotherapy v 6.6 days without chest physiotherapy; reported as not significant, P value not reported). The third RCT identified by the review (32 children) found no significant improvement in clinical score with chest physiotherapy compared with no chest physiotherapy on the fifth day of the study or at discharge if earlier (mean difference between the clinical scores: +0.13, 95% CI -0.71 to +0.97). The clinical score was constructed from five clinical variables: respiratory rate, heart rate, lung auscultation, and accessory muscle use. It is not clear how the final score was calculated. The RCT also found no significant difference between groups in length of stay (mean length of stay: 4 days with chest physiotherapy v 3.9 days without chest physiotherapy; mean difference 0.13 days, 95% CI -1.00 to +1.26)
The authors in the review concluded that chest physiotherapy cannot be recommended for hospitalised children with bronchiolitis. Pooling the data could have reduced the chance of a type II error (false negative). However, such error is unlikely for length of hospital stay, since two of the RCTs had a large enough sample size to find a difference of 1 day between treatments.
Chest physiotherapy New option added for which one systematic review identified three RCTs. None of the RCTs found that chest physiotherapy improved clinical scores or reduced length of hospital stay. However, more data are awaited before a definitive assessment of effectiveness can be reached. Categorised as Unknown effectiveness.
SYMPTOM IMPROVEMENT Compared with no surfactants: Surfactants may be more effective than no surfactants at decreasing the intensive care length of stay in mechanically ventilated infants and children with viral bronchiolitis, but not in reducing the duration of ventilation or the duration of hospitalisation ( low-quality evidence ).
We found one systematic review (search date 2006, 3 RCTs, 79 children). Included trials compared different types of surfactant (porcine in two trials and bovine in the third) in mechanically ventilated infants and children with viral bronchiolitis. No deaths were reported in any of the trials. The review found no significant difference in duration of ventilation between surfactants and no surfactants (2 RCTs, WMD –2.6 days, 95% CI –5.34 to +0.18 days; P = 0.07). Administering surfactants significantly decreased intensive care length of stay (2 RCTs, WMD –3.3 days, 95% CI –6.38 to –0.23 days; P = 0.04). However, there was strong heterogeneity between the RCTs meta-analysed. One of the trials in the review found no significant difference in the duration of hospitalisation between surfactants and no surfactants (13 days with surfactants v 17 days without surfactants; P = 0.3).
The authors of the review concluded that it is difficult to draw strong inferences about the effect of surfactant in this population, and that there is a need for adequately powered trials in this area.
Surfactants New option added for which we found one systematic review. The review performed a meta-analysis, which suggested that surfactants were effective but there was was strong heterogeneity between the RCTs meta-analysed. We therefore cannot make a firm judgment about the effectiveness of surfactants. Categorised as Unknown effectiveness.
We found no direct information from RCTs about montelukast in the treatment of children with bronchiolitis.
We found no systematic review or RCTs assessing the outcomes of interest for this review.
We found no RCTs.
One RCT was found, but it evaluated only one outcome (reactive airways disease after bronchiolitis), which is not one of interest for this review.
No new evidence