BACKGROUND: Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review.
OBJECTIVES: To investigate efficacy and tolerability of nebulised hypertonic saline treatment in people with cystic fibrosis (CF) compared to placebo or other treatments that enhance mucociliary clearance.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases. Most recent search: 25 April 2022.
SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).
DATA COLLECTION AND ANALYSIS: Two authors independently reviewed all identified trials and data, and assessed trial quality. We assessed the certainty of the evidence using GRADE. For cross-over trials we stipulated a one-week washout period. We planned to use results from a paired analysis in the review, but this was only possible in one trial. For other cross-over trials, we chose to treat the trials as if they were parallel.
MAIN RESULTS: We included 24 trials (1318 participants, aged one month to 56 years); we excluded 29 trials, two trials are ongoing and six are awaiting classification. We judged 15 of the 24 included trials to have a high risk of bias due to participants' ability to discern the taste of the solutions. Hypertonic saline 3% to 7% versus placebo (stable disease) We are uncertain whether the regular use of nebulised hypertonic saline in stable lung disease leads to an improvement in forced expiratory volume in one second (FEV1) % predicted at four weeks, (mean difference (MD) 3.30%, 95% confidence interval (CI) 0.71 to 5.89; 4 trials, 246 participants; very low-certainty evidence). In preschool children we found no difference in lung clearance index (LCI) at four weeks, but a small improvement after 48 weeks of treatment with hypertonic saline compared to isotonic saline (MD -0.60, 95% CI -1.00 to -0.19; 2 trials, 192 participants). We are also uncertain whether hypertonic saline made a difference to mucociliary clearance, pulmonary exacerbations or adverse events compared to placebo. Hypertonic saline versus control (acute exacerbation) Two trials compared hypertonic saline to control, but only one provided data. There may be little or no difference in lung function measured by FEV1 % predicted after hypertonic saline compared to isotonic saline (MD 5.10%, 95% CI -14.67 to 24.87; 1 trial, 130 participants). Neither trial reported any deaths or measures of sputum clearance. There were no serious adverse events. Hypertonic saline versus rhDNase Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two trials (61 participants) provided data for inclusion in the review. We are uncertain whether there was an effect of hypertonic saline on FEV1 % predicted after three weeks (MD 1.60%, 95% CI -7.96 to 11.16; 1 trial, 14 participants; very low-certainty evidence). At three months, rhDNase may lead to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease (MD 8.00%, 95% CI 2.00 to 14.00; low-certainty evidence). We are uncertain whether adverse events differed between the two treatments. No deaths were reported. Hypertonic saline versus amiloride One trial (12 participants) compared hypertonic saline to amiloride but did not report on most of our outcomes. The trial found that there was no difference between treatments in measures of sputum clearance (very low-certainty evidence). Hypertonic saline compared with sodium-2-mercaptoethane sulphonate (Mistabron®) One trial (29 participants) compared hypertonic saline to sodium-2-mercaptoethane sulphonate. The trial did not measure our primary outcomes. There was no difference between treatments in any measures of sputum clearance, courses of antibiotics or adverse events (very low-certainty evidence). Hypertonic saline versus mannitol One trial (12 participants) compared hypertonic saline to mannitol, but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-certainty evidence). Hypertonic saline versus xylitol Two trials compared hypertonic saline to xylitol, but we are uncertain whether there is any difference in FEV1 % predicted or median time to exacerbation between groups (very low-certainty evidence). No other outcomes were reported in the review. Hypertonic saline 7% versus hypertonic saline 3% We are uncertain whether there was an improvement in FEV1 % predicted after treatment with 7% hypertonic saline compared with 3% (very low-certainty evidence).
AUTHORS' CONCLUSIONS: We are very uncertain if regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (three trials; very low-certainty evidence); there was no difference seen at 48 weeks (one trial; low-certainty evidence). Hypertonic saline improved LCI modestly in children under the age of six years. Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function than hypertonic saline at three months; qualifying this, we highlight that while the study did demonstrate that the improvement in FEV1 was greater with daily rhDNase, there were no differences seen in any of the secondary outcomes. Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the certainty of the evidence ranged from very low to low at best, according to the GRADE criteria. The role of hypertonic saline in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy now needs to be considered, and future research needs to focus on this aspect.
BACKGROUND: Acute bronchiolitis is the leading cause of medical emergencies during winter months in infants younger than 24 months old. Chest physiotherapy is sometimes used to assist infants in the clearance of secretions in order to decrease ventilatory effort. This is an update of a Cochrane Review first published in 2005 and updated in 2006, 2012, and 2016.
OBJECTIVES: To determine the efficacy of chest physiotherapy in infants younger than 24 months old with acute bronchiolitis. A secondary objective was to determine the efficacy of different techniques of chest physiotherapy (vibration and percussion, passive exhalation, or instrumental).
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Web of Science, PEDro (October 2011 to 20 April 2022), and two trials registers (5 April 2022).
SELECTION CRITERIA: Randomised controlled trials (RCTs) in which chest physiotherapy was compared to control (conventional medical care with no physiotherapy intervention) or other respiratory physiotherapy techniques in infants younger than 24 months old with bronchiolitis.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.
MAIN RESULTS: Our update of the searches dated 20 April 2022 identified five new RCTs with 430 participants. We included a total of 17 RCTs (1679 participants) comparing chest physiotherapy with no intervention or comparing different types of physiotherapy. Five trials (246 participants) assessed percussion and vibration techniques plus postural drainage (conventional chest physiotherapy), and 12 trials (1433 participants) assessed different passive flow-oriented expiratory techniques, of which three trials (628 participants) assessed forced expiratory techniques, and nine trials (805 participants) assessed slow expiratory techniques. In the slow expiratory subgroup, two trials (78 participants) compared the technique with instrumental physiotherapy techniques, and two recent trials (116 participants) combined slow expiratory techniques with rhinopharyngeal retrograde technique (RRT). One trial used RRT alone as the main component of the physiotherapy intervention. Clinical severity was mild in one trial, severe in four trials, moderate in six trials, and mild to moderate in five trials. One study did not report clinical severity. Two trials were performed on non-hospitalised participants. Overall risk of bias was high in six trials, unclear in five, and low in six trials. The analyses showed no effects of conventional techniques on change in bronchiolitis severity status, respiratory parameters, hours with oxygen supplementation, or length of hospital stay (5 trials, 246 participants). Regarding instrumental techniques (2 trials, 80 participants), one trial observed similar results in bronchiolitis severity status when comparing slow expiration to instrumental techniques (mean difference 0.10, 95% confidence interval (C) -0.17 to 0.37). Forced passive expiratory techniques failed to show an effect on bronchiolitis severity in time to recovery (2 trials, 509 participants; high-certainty evidence) and time to clinical stability (1 trial, 99 participants; high-certainty evidence) in infants with severe bronchiolitis. Important adverse effects were reported with the use of forced expiratory techniques. Regarding slow expiratory techniques, a mild to moderate improvement was observed in bronchiolitis severity score (standardised mean difference -0.43, 95% CI -0.73 to -0.13; I2 = 55%; 7 trials, 434 participants; low-certainty evidence). Also, in one trial an improvement in time to recovery was observed with the use of slow expiratory techniques. No benefit was observed in length of hospital stay, except for one trial which showed a one-day reduction. No effects were shown or reported for other clinical outcomes such as duration on oxygen supplementation, use of bronchodilators, or parents' impression of physiotherapy benefit.
AUTHORS' CONCLUSIONS: We found low-certainty evidence that passive slow expiratory technique may result in a mild to moderate improvement in bronchiolitis severity when compared to control. This evidence comes mostly from infants with moderately acute bronchiolitis treated in hospital. The evidence was limited with regard to infants with severe bronchiolitis and those with moderately severe bronchiolitis treated in ambulatory settings. We found high-certainty evidence that conventional techniques and forced expiratory techniques result in no difference in bronchiolitis severity or any other outcome. We found high-certainty evidence that forced expiratory techniques in infants with severe bronchiolitis do not improve their health status and can lead to severe adverse effects. Currently, the evidence regarding new physiotherapy techniques such as RRT or instrumental physiotherapy is scarce, and further trials are needed to determine their effects and potential for use in infants with moderate bronchiolitis, as well as the potential additional effect of RRT when combined with slow passive expiratory techniques. Finally, the effectiveness of combining chest physiotherapy with hypertonic saline should also be investigated.
BACKGROUND: Airway oedema (swelling) and mucus plugging are the principal pathological features in infants with acute viral bronchiolitis. Nebulised hypertonic saline solution (≥ 3%) may reduce these pathological changes and decrease airway obstruction. This is an update of a review first published in 2008, and updated in 2010, 2013, and 2017.
OBJECTIVES: To assess the effects of nebulised hypertonic (≥ 3%) saline solution in infants with acute bronchiolitis.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily, Embase, CINAHL, LILACS, and Web of Science on 13 January 2022. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 13 January 2022.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs using nebulised hypertonic saline alone or in conjunction with bronchodilators as an active intervention and nebulised 0.9% saline or standard treatment as a comparator in children under 24 months with acute bronchiolitis. The primary outcome for inpatient trials was length of hospital stay, and the primary outcome for outpatients or emergency department (ED) trials was rate of hospitalisation.
DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, and assessment of risk of bias in included studies. We conducted random-effects model meta-analyses using Review Manager 5. We used mean difference (MD), risk ratio (RR), and their 95% confidence intervals (CI) as effect size metrics.
MAIN RESULTS: We included six new trials (N = 1010) in this update, bringing the total number of included trials to 34, involving 5205 infants with acute bronchiolitis, of whom 2727 infants received hypertonic saline. Eleven trials await classification due to insufficient data for eligibility assessment. All included trials were randomised, parallel-group, controlled trials, of which 30 were double-blinded. Twelve trials were conducted in Asia, five in North America, one in South America, seven in Europe, and nine in Mediterranean and Middle East regions. The concentration of hypertonic saline was defined as 3% in all but six trials, in which 5% to 7% saline was used. Nine trials had no funding, and five trials were funded by sources from government or academic agencies. The remaining 20 trials did not provide funding sources. Hospitalised infants treated with nebulised hypertonic saline may have a shorter mean length of hospital stay compared to those treated with nebulised normal (0.9%) saline or standard care (mean difference (MD) -0.40 days, 95% confidence interval (CI) -0.69 to -0.11; 21 trials, 2479 infants; low-certainty evidence). Infants who received hypertonic saline may also have lower postinhalation clinical scores than infants who received normal saline in the first three days of treatment (day 1: MD -0.64, 95% CI -1.08 to -0.21; 10 trials (1 outpatient, 1 ED, 8 inpatient trials), 893 infants; day 2: MD -1.07, 95% CI -1.60 to -0.53; 10 trials (1 outpatient, 1 ED, 8 inpatient trials), 907 infants; day 3: MD -0.89, 95% CI -1.44 to -0.34; 10 trials (1 outpatient, 9 inpatient trials), 785 infants; low-certainty evidence). Nebulised hypertonic saline may reduce the risk of hospitalisation by 13% compared with nebulised normal saline amongst infants who were outpatients and those treated in the ED (risk ratio (RR) 0.87, 95% CI 0.78 to 0.97; 8 trials, 1760 infants; low-certainty evidence). However, hypertonic saline may not reduce the risk of readmission to hospital up to 28 days after discharge (RR 0.83, 95% CI 0.55 to 1.25; 6 trials, 1084 infants; low-certainty evidence). We are uncertain whether infants who received hypertonic saline have a lower number of days to resolution of wheezing compared to those who received normal saline (MD -1.16 days, 95% CI -1.43 to -0.89; 2 trials, 205 infants; very low-certainty evidence), cough (MD -0.87 days, 95% CI -1.31 to -0.44; 3 trials, 363 infants; very low-certainty evidence), and pulmonary moist crackles (MD -1.30 days, 95% CI -2.28 to -0.32; 2 trials, 205 infants; very low-certainty evidence). Twenty-seven trials presented safety data: 14 trials (1624 infants; 767 treated with hypertonic saline, of which 735 (96%) co-administered with bronchodilators) did not report any adverse events, and 13 trials (2792 infants; 1479 treated with hypertonic saline, of which 416 (28%) co-administered with bronchodilators and 1063 (72%) hypertonic saline alone) reported at least one adverse event such as worsening cough, agitation, bronchospasm, bradycardia, desaturation, vomiting and diarrhoea, most of which were mild and resolved spontaneously (low-certainty evidence).
AUTHORS' CONCLUSIONS: Nebulised hypertonic saline may modestly reduce length of stay amongst infants hospitalised with acute bronchiolitis and may slightly improve clinical severity score. Treatment with nebulised hypertonic saline may also reduce the risk of hospitalisation amongst outpatients and ED patients. Nebulised hypertonic saline seems to be a safe treatment in infants with bronchiolitis with only minor and spontaneously resolved adverse events, especially when administered in conjunction with a bronchodilator. The certainty of the evidence was low to very low for all outcomes, mainly due to inconsistency and risk of bias.
Respiratory syncytial virus (RSV) is a major worldwide cause of morbidity and mortality in children under five years of age. Evidence-based management guidelines suggest that there is no effective treatment for RSV lower respiratory tract infection (LRTI) and that supportive care, ie, hydration and oxygenation, remains the cornerstone of clinical management. However, RSV treatments in development in the past decade include 10 vaccines and 11 therapeutic agents in active clinical trials. Maternal vaccination is particularly relevant because the most severe disease occurs within the first 6 months of life, when children are unlikely to benefit from active immunisation. We must optimise the implementation of novel RSV therapeutics by understanding the target populations, showing safety, and striving for acceptable pricing in the context of this worldwide health problem. In this Review, we outline the limitations of RSV LRTI management, the drugs in development, and the remaining challenges related to study design, regulatory approval, and implementation.
BACKGROUND: Bronchiolitis is the leading cause of hospitalisation among infants in high-income countries. Acute viral bronchiolitis is associated with airway obstruction and turbulent gas flow. Heliox, a mixture of oxygen and the inert gas helium, may improve gas flow through high-resistance airways and decrease the work of breathing. In this review, we selected trials that objectively assessed the effect of the addition of heliox to standard medical care for acute bronchiolitis.
OBJECTIVES: To assess heliox inhalation therapy in addition to standard medical care for acute bronchiolitis in infants with respiratory distress, as measured by clinical endpoints (in particular the rate of endotracheal intubation, the rate of emergency department discharge, the length of treatment for respiratory distress) and pulmonary function testing (mainly clinical respiratory scores).
SEARCH METHODS: We searched CENTRAL (2015, Issue 2), MEDLINE (1966 to March week 3, 2015), EMBASE (1974 to March 2015), LILACS (1982 to March 2015) and the National Institutes of Health (NIH) website (May 2009).
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of heliox in infants with acute bronchiolitis.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality.
MAIN RESULTS: We included seven trials involving 447 infants younger than two years with respiratory distress secondary to viral bronchiolitis. All children were recruited from a paediatric intensive care unit (PICU; 378 infants), except in one trial (emergency department; 69 infants). All children were younger than two (under nine months in two trials and under three months in one trial). Positive tests for respiratory syncytial virus (RSV) were required for inclusion in five trials. The two other trials were carried out in the bronchiolitis seasons. Seven different protocols were used for inhalation therapy with heliox.When heliox was used in the PICU, we observed no significant reduction in the rate of intubation: risk ratio (RR) 2.73 (95% confidence interval (CI) 0.96 to 7.75, four trials, 408 infants, low quality evidence). When heliox inhalation was used in the emergency department, we observed no increase in the rate of discharge: RR 0.51 (95% CI 0.17 to 1.55, one trial, 69 infants, moderate quality evidence).There was no decrease in the length of treatment for respiratory distress: mean difference (MD) -0.19 days (95% CI -0.56 to 0.19, two trials, 320 infants, moderate quality evidence). However, in the subgroup of infants who were started on nasal continuous positive airway pressure (nCPAP) right from the start, because of severe respiratory distress, heliox therapy reduced the length of treatment: MD -0.76 days (95% CI -1.45 to -0.08, one trial, 21 infants, low quality evidence). No adverse events related to heliox inhalation were reported.We found that infants treated with heliox inhalation had a significantly lower mean clinical respiratory score in the first hour after starting treatment when compared to those treated with air or oxygen inhalation: MD -1.04 (95% CI -1.60 to -0.48, four trials, 138 infants, moderate quality evidence). This outcome had statistical heterogeneity, which remained even after removing the study using a standard high-concentration reservoir mask. Several factors may explain this heterogeneity, including first the limited number of patients in each trial, and the wide differences in the baseline severity of disease between studies, with the modified Wood Clinical Asthma Score (m-WCAS) in infants treated with heliox ranging from less than two to more than seven.
AUTHORS' CONCLUSIONS: Current evidence suggests that the addition of heliox therapy may significantly reduce a clinical score evaluating respiratory distress in the first hour after starting treatment in infants with acute RSV bronchiolitis. We noticed this beneficial effect regardless of which heliox inhalation protocol was used. Nevertheless, there was no reduction in the rate of intubation, in the rate of emergency department discharge, or in the length of treatment for respiratory distress. Heliox could reduce the length of treatment in infants requiring CPAP for severe respiratory distress. Further studies with homogeneous logistics in their heliox application are needed. Inclusion criteria must include a clinical severity score that reflects severe respiratory distress to avoid inclusion of children with mild bronchiolitis who may not benefit from heliox inhalation. Such studies would provide the necessary information as to the appropriate place for heliox in the therapeutic schedule for severe bronchiolitis.
BACKGROUND: Bronchiolitis is an acute inflammatory illness of the bronchioles common among infants and young children. It is often caused by the respiratory syncytial virus (RSV). Management of bronchiolitis varies between clinicians, reflecting the lack of evidence for a specific treatment approach. The leukotriene pathway has been reported to be involved in the pathogenesis of bronchiolitis. Leukotriene inhibitors such as montelukast have been used in infants and young children with bronchiolitis. However, the results from limited randomised controlled trials (RCTs) are controversial and necessitate a thorough evaluation of their efficacy for bronchiolitis in infants and young children.
OBJECTIVES: To assess the efficacy and safety of leukotriene inhibitors for bronchiolitis in infants and young children.
SEARCH METHODS: We searched CENTRAL (2014, Issue 5), MEDLINE (1946 to April week 4, 2014), EMBASE (1974 to May 2014), CINAHL (1981 to May 2014), LILACS (1982 to May 2014), Web of Science (1985 to May 2014), WHO ICTRP and ClinicalTrials.gov (6 May 2014).
SELECTION CRITERIA: RCTs comparing leukotriene inhibitors versus placebo or another intervention in infants and young children under two years of age diagnosed with bronchiolitis. Our primary outcomes were length of hospital stay and all-cause mortality. Secondary outcomes included clinical severity score, percentage of symptom-free days, percentage of children requiring ventilation, oxygen saturation, recurrent wheezing, respiratory rate and clinical adverse effects.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane Collaboration methodological practices. Two authors independently assessed trial eligibility and extracted data, such as general information, participant characteristics, interventions and outcomes. We assessed risk of bias and graded the quality of the evidence. We used Review Manager software to pool results and chose random-effects models for meta-analysis.
MAIN RESULTS: We included five studies with a total of 1296 participants under two years of age hospitalised with bronchiolitis. Two studies with low risk of bias compared 4 mg montelukast (a leukotriene inhibitor) daily use from admission until discharge with a matching placebo. Both selected length of hospital stay as a primary outcome and clinical severity score as a secondary outcome. However, the effects of leukotriene inhibitors on length of hospital stay and clinical severity score were uncertain due to considerable heterogeneity between the study results and wide confidence intervals around the estimated effects (hospital stay: mean difference (MD) -0.95 days, 95% confidence interval (CI) -3.08 to 1.19, P value = 0.38, low quality evidence; clinical severity score on day two: MD -0.57, 95% CI -2.37 to 1.23, P value = 0.53, low quality evidence; clinical severity score on day three: MD 0.17, 95% CI -1.93 to 2.28, P value = 0.87, low quality evidence). The other three studies compared montelukast for several weeks for preventing post-bronchiolitis symptoms with placebo. We assessed one study as low risk of bias, whereas we assessed the other two studies as having a high risk of attrition bias. Due to the significant clinical heterogeneity in severity of disease, duration of treatment, outcome measurements and timing of assessment, we did not pool the results. Individual analyses of these studies did not show significant differences between the leukotriene inhibitors group and the control group in symptom-free days and incidence of recurrent wheezing. One study of 952 children reported two deaths in the leukotriene inhibitors group: neither was determined to be drug-related. No data were available on the percentage of children requiring ventilation, oxygen saturation and respiratory rate. Finally, three studies reported adverse events including diarrhoea, wheezing shortly after administration and rash. No differences were reported between the study groups.
AUTHORS' CONCLUSIONS: The current evidence does not allow definitive conclusions to be made about the effects of leukotriene inhibitors on length of hospital stay and clinical severity score in infants and young children with bronchiolitis. The quality of the evidence was low due to inconsistency (unexplained high levels of statistical heterogeneity) and imprecision arising from small sample sizes and wide confidence intervals, which did not rule out a null effect or harm. Data on symptom-free days and incidence of recurrent wheezing were from single studies only. Further large studies are required. We identified one registered ongoing study, which may make a contribution in the updates of this review.
Acute bronchiolitis is the leading cause of lower respiratory tract infection and hospitalization in children less than 1 year of age worldwide. It is usually a mild disease, but some children may develop severe symptoms, requiring hospital admission and ventilatory support in the ICU. Infants with pre-existing risk factors (prematurity, bronchopulmonary dysplasia, congenital heart diseases and immunodeficiency) may be predisposed to a severe form of the disease. Clinical diagnosis of bronchiolitis is manly based on medical history and physical examination (rhinorrhea, cough, crackles, wheezing and signs of respiratory distress). Etiological diagnosis, with antigen or genome detection to identify viruses involved, may have a role in reducing hospital transmission of the infection. Criteria for hospitalization include low oxygen saturation (<90-92%), moderate-to-severe respiratory distress, dehydration and presence of apnea. Children with pre-existing risk factors should be carefully assessed.To date, there is no specific treatment for viral bronchiolitis, and the mainstay of therapy is supportive care. This consists of nasal suctioning and nebulized 3% hypertonic saline, assisted feeding and hydration, humidified O2 delivery. The possible role of any pharmacological approach is still debated, and till now there is no evidence to support the use of bronchodilators, corticosteroids, chest physiotherapy, antibiotics or antivirals. Nebulized adrenaline may be sometimes useful in the emergency room. Nebulized adrenaline can be useful in the hospital setting for treatment as needed. Lacking a specific etiological treatment, prophylaxis and prevention, especially in children at high risk of severe infection, have a fundamental role. Environmental preventive measures minimize viral transmission in hospital, in the outpatient setting and at home. Pharmacological prophylaxis with palivizumab for RSV bronchiolitis is indicated in specific categories of children at risk during the epidemic period. Viral bronchiolitis, especially in the case of severe form, may correlate with an increased incidence of recurrent wheezing in pre-schooled children and with asthma at school age.The aim of this document is to provide a multidisciplinary update on the current recommendations for the management and prevention of bronchiolitis, in order to share useful indications, identify gaps in knowledge and drive future research.
BACKGROUND: Bronchiolitis is a serious, potentially life-threatening respiratory illness commonly affecting babies. It is often caused by respiratory syncytial virus (RSV). Antibiotics are not recommended for bronchiolitis unless there is concern about complications such as secondary bacterial pneumonia or respiratory failure. Nevertheless, they are often used.
OBJECTIVES: To evaluate the effectiveness of antibiotics for bronchiolitis in children under two years of age compared to placebo or other interventions.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 6), which includes the Cochrane Acute Respiratory Infection Group's Specialised Register, and the Database of Abstracts of Reviews of Effects, MEDLINE (1966 to June 2014), EMBASE (1990 to June 2014) and Current Contents (2001 to June 2014).
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing antibiotics to placebo in children under two years diagnosed with bronchiolitis, using clinical criteria (including respiratory distress preceded by coryzal symptoms with or without fever). Primary clinical outcomes included time to resolution of signs or symptoms (pulmonary markers included respiratory distress, wheeze, crepitations, oxygen saturation and fever). Secondary outcomes included hospital admissions, length of hospital stay, readmissions, complications or adverse events and radiological findings.
DATA COLLECTION AND ANALYSIS: Two review authors independently analysed the search results.
MAIN RESULTS: We included seven studies with a total of 824 participants. The results of these seven included studies were often heterogeneous, which generally precluded meta-analysis, except for deaths, length of supplemental oxygen use and length of hospital admission.
In this update, we included two new studies (281 participants), both comparing azithromycin with placebo. They found no significant difference for length of hospital stay, duration of oxygen requirement and readmission. These results were similar to an older study (52 participants) that demonstrated no significant difference comparing ampicillin and placebo for length of illness.
One small study (21 participants) with higher risk of bias randomised children with proven RSV infection to clarithromycin or placebo and found a trend towards a reduction in hospital readmission with clarithromycin.
The three studies providing adequate data for days of supplementary oxygen showed no difference between antibiotics and placebo (pooled mean difference (MD) (days) -0.20; 95% confidence interval (CI) -0.72 to 0.33). The three studies providing adequate data for length of hospital stay, similarly showed no difference between antibiotics (azithromycin) and placebo (pooled MD (days) -0.58; 95% CI -1.18 to 0.02).
Two studies randomised children to intravenous ampicillin, oral erythromycin and control and found no difference for most symptom measures.
There were no deaths reported in any of the arms of the seven included studies. No other adverse effects were reported.
AUTHORS' CONCLUSIONS: This review did not find sufficient evidence to support the use of antibiotics for bronchiolitis, although research may be justified to identify a subgroup of patients who may benefit from antibiotics. Further research may be better focused on determining the reasons that clinicians use antibiotics so readily for bronchiolitis, how to reduce their use and how to reduce clinician anxiety about not using antibiotics.
BACKGROUND: Previous systematic reviews have not shown clear benefit of glucocorticoids for acute viral bronchiolitis, but their use remains considerable. Recent large trials add substantially to current evidence and suggest novel glucocorticoid-including treatment approaches. OBJECTIVES: To review the efficacy and safety of systemic and inhaled glucocorticoids in children with acute viral bronchiolitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2012, Issue 12), MEDLINE (1950 to January week 2, 2013), EMBASE (1980 to January 2013), LILACS (1982 to January 2013), Scopus® (1823 to January 2013) and IRAN MedEx (1998 to November 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing short-term systemic or inhaled glucocorticoids versus placebo or another intervention in children under 24 months with acute bronchiolitis (first episode with wheezing). Our primary outcomes were: admissions by days 1 and 7 for outpatient studies; and length of stay (LOS) for inpatient studies. Secondary outcomes included clinical severity parameters, healthcare use, pulmonary function, symptoms, quality of life and harms. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on study and participant characteristics, interventions and outcomes. We assessed risk of bias and graded strength of evidence. We meta-analysed inpatient and outpatient results separately using random-effects models. We pre-specified subgroup analyses, including the combined use of bronchodilators used in a protocol. MAIN RESULTS: We included 17 trials (2596 participants); three had low overall risk of bias. Baseline severity, glucocorticoid schemes, comparators and outcomes were heterogeneous. Glucocorticoids did not significantly reduce outpatient admissions by days 1 and 7 when compared to placebo (pooled risk ratios (RRs) 0.92; 95% confidence interval (CI) 0.78 to 1.08 and 0.86; 95% CI 0.7 to 1.06, respectively). There was no benefit in LOS for inpatients (mean difference -0.18 days; 95% CI -0.39 to 0.04). Unadjusted results from a large factorial low risk of bias RCT found combined high-dose systemic dexamethasone and inhaled epinephrine reduced admissions by day 7 (baseline risk of admission 26%; RR 0.65; 95% CI 0.44 to 0.95; number needed to treat 11; 95% CI 7 to 76), with no differences in short-term adverse effects. No other comparisons showed relevant differences in primary outcomes. AUTHORS' CONCLUSIONS: Current evidence does not support a clinically relevant effect of systemic or inhaled glucocorticoids on admissions or length of hospitalisation. Combined dexamethasone and epinephrine may reduce outpatient admissions, but results are exploratory and safety data limited. Future research should further assess the efficacy, harms and applicability of combined therapy.
BACKGROUND: Bronchiolitis is one of the most common respiratory problems in the first year of life. The sputum of infants with bronchiolitis has increased deoxyribonucleic acid (DNA) content, leading to mucous plugging and airway obstruction. Recombinant human deoxyribonuclease (rhDNase), an enzyme that digests extracellular DNA, might aid the clearance of mucus and relieve peripheral airway obstruction.
OBJECTIVES: To determine the effect of nebulised rhDNase on the severity and duration of viral bronchiolitis in children younger than 24 months of age in the hospital setting.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2012, Issue 7 which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to July Week 4, 2012), EMBASE (1974 to August 2012) and LILACS (1982 to August 2012).
SELECTION CRITERIA: Randomised controlled trials (RCTs) using nebulised rhDNase alone or with concomitant therapy in children younger than 24 months of age hospitalised with acute bronchiolitis.
DATA COLLECTION AND ANALYSIS: Two review authors independently performed literature searches, assessed trial quality and extracted data. We obtained unpublished data from trial authors. We used Review Manager 5.1 to pool treatment effects expressed as the mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI).
MAIN RESULTS: Three RCTs (333 participants) were identified, two of which were multicentre trials comprising only participants positive for respiratory syncytial virus (RSV). The other trial enrolled participants clinically diagnosed with bronchiolitis from a hospital in Italy. All studies used 2.5 mL (1 mg/mL) of nebulised rhDNase compared with placebo either as a daily or a twice daily dose. Adjunctive therapy included nebulised salbutamol, steroids, supplemental oxygen, intravenous fluids or tube feeding, nasal washing, nasal decongestants and antibiotics.
Overall, nebulised rhDNase showed no benefit in clinically meaningful outcomes. Meta-analysis favoured the control group with a shorter duration of hospital stay (MD 0.50; 95% CI 0.10 to 0.90, P = 0.01) and better clinical score improvement (SMD -0.24; 95% CI -0.50 to 0.01, P = 0.06). The largest trial showed no difference in supplemental oxygen use or intensive care unit (ICU) admission.
In one RCT, four out of 11 patients in the treatment group had atelectasis. Two of these patients showed distinctive clinical improvement after nebulised rhDNase.
There was no significant difference in adverse events. These included temporary desaturation, temporary coughing, increased coughing, facial rash, hoarseness, dyspnoea and bad taste, reported in a total of 11 patients from both treatment groups.
AUTHORS' CONCLUSIONS: The results based on the three included studies in this review did not support the use of nebulised rhDNase in children under 24 months of age hospitalised with acute bronchiolitis. In these patients, treatment did not shorten the length of hospitalisation or improve clinical outcomes. It might have a role in severe bronchiolitis complicated by atelectasis, but further clinical studies would need to be performed.
Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review.
OBJECTIVES:
To investigate efficacy and tolerability of nebulised hypertonic saline treatment in people with cystic fibrosis (CF) compared to placebo or other treatments that enhance mucociliary clearance.
SEARCH METHODS:
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases. Most recent search: 25 April 2022.
SELECTION CRITERIA:
We included randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).
DATA COLLECTION AND ANALYSIS:
Two authors independently reviewed all identified trials and data, and assessed trial quality. We assessed the certainty of the evidence using GRADE. For cross-over trials we stipulated a one-week washout period. We planned to use results from a paired analysis in the review, but this was only possible in one trial. For other cross-over trials, we chose to treat the trials as if they were parallel.
MAIN RESULTS:
We included 24 trials (1318 participants, aged one month to 56 years); we excluded 29 trials, two trials are ongoing and six are awaiting classification. We judged 15 of the 24 included trials to have a high risk of bias due to participants' ability to discern the taste of the solutions. Hypertonic saline 3% to 7% versus placebo (stable disease) We are uncertain whether the regular use of nebulised hypertonic saline in stable lung disease leads to an improvement in forced expiratory volume in one second (FEV1) % predicted at four weeks, (mean difference (MD) 3.30%, 95% confidence interval (CI) 0.71 to 5.89; 4 trials, 246 participants; very low-certainty evidence). In preschool children we found no difference in lung clearance index (LCI) at four weeks, but a small improvement after 48 weeks of treatment with hypertonic saline compared to isotonic saline (MD -0.60, 95% CI -1.00 to -0.19; 2 trials, 192 participants). We are also uncertain whether hypertonic saline made a difference to mucociliary clearance, pulmonary exacerbations or adverse events compared to placebo. Hypertonic saline versus control (acute exacerbation) Two trials compared hypertonic saline to control, but only one provided data. There may be little or no difference in lung function measured by FEV1 % predicted after hypertonic saline compared to isotonic saline (MD 5.10%, 95% CI -14.67 to 24.87; 1 trial, 130 participants). Neither trial reported any deaths or measures of sputum clearance. There were no serious adverse events. Hypertonic saline versus rhDNase Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two trials (61 participants) provided data for inclusion in the review. We are uncertain whether there was an effect of hypertonic saline on FEV1 % predicted after three weeks (MD 1.60%, 95% CI -7.96 to 11.16; 1 trial, 14 participants; very low-certainty evidence). At three months, rhDNase may lead to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease (MD 8.00%, 95% CI 2.00 to 14.00; low-certainty evidence). We are uncertain whether adverse events differed between the two treatments. No deaths were reported. Hypertonic saline versus amiloride One trial (12 participants) compared hypertonic saline to amiloride but did not report on most of our outcomes. The trial found that there was no difference between treatments in measures of sputum clearance (very low-certainty evidence). Hypertonic saline compared with sodium-2-mercaptoethane sulphonate (Mistabron®) One trial (29 participants) compared hypertonic saline to sodium-2-mercaptoethane sulphonate. The trial did not measure our primary outcomes. There was no difference between treatments in any measures of sputum clearance, courses of antibiotics or adverse events (very low-certainty evidence). Hypertonic saline versus mannitol One trial (12 participants) compared hypertonic saline to mannitol, but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-certainty evidence). Hypertonic saline versus xylitol Two trials compared hypertonic saline to xylitol, but we are uncertain whether there is any difference in FEV1 % predicted or median time to exacerbation between groups (very low-certainty evidence). No other outcomes were reported in the review. Hypertonic saline 7% versus hypertonic saline 3% We are uncertain whether there was an improvement in FEV1 % predicted after treatment with 7% hypertonic saline compared with 3% (very low-certainty evidence).
AUTHORS' CONCLUSIONS:
We are very uncertain if regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (three trials; very low-certainty evidence); there was no difference seen at 48 weeks (one trial; low-certainty evidence). Hypertonic saline improved LCI modestly in children under the age of six years. Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function than hypertonic saline at three months; qualifying this, we highlight that while the study did demonstrate that the improvement in FEV1 was greater with daily rhDNase, there were no differences seen in any of the secondary outcomes. Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the certainty of the evidence ranged from very low to low at best, according to the GRADE criteria. The role of hypertonic saline in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy now needs to be considered, and future research needs to focus on this aspect.
