Wheezing in preschool children is very common, with a wide differential diagnosis. It is essentia... more Wheezing in preschool children is very common, with a wide differential diagnosis. It is essential to be sure of the exact sound that parents are describing; the term ‘wheeze‘ is often applied to non-specific sounds. Structural airway disease such as vascular ring should be considered. Thereafter we propose that umbrella terms for preschool wheeze should be abandoned in favour of ‘Hargreave phenotyping’, in which the presence and extent of the components of infection, inflammation, variable airflow obstruction, and fixed airflow obstruction are determined as far as is possible, rather than using a general umbrella term such as ‘asthma’. The justification for this approach is that it leads to a logical approach to treatment in the disparate airway diseases presenting in the preschool years, and should hopefully prevent over-treatment with inhaled corticosteroids. If, despite this approach, doubt remains as to the nature of the airway disease, then a therapeutic trial of treatment is ...
When a child with severe asthma (asthma defined clinically for the purposes of this review as whe... more When a child with severe asthma (asthma defined clinically for the purposes of this review as wheeze, breathlessness, and chest tightness sometimes with cough) does not respond to treatment, it is important to be sure that an alternative or additional diagnosis is not being missed. In school age children, the next step is a detailed protocolized assessment to determine the nature of the problem, whether within the airway or related to co-morbidities or social/environmental factors, in order to personalize the treatment. For example, those with refractory difficult asthma due to persistent non-adherence may benefit from using budesonide and formoterol combined in a single inhaler [single maintenance and reliever treatment (SMART)] as both a reliever and preventer. For those with steroid-resistant Type 2 airway inflammation, the use of biologicals such as omalizumab and mepolizumab should be considered, but for mepolizumab at least, there is a paucity of pediatric data. Protocols are ...
measurements of lung clearance index (LCI) The data of Nyilas et al1 relating nitrogen washout me... more measurements of lung clearance index (LCI) The data of Nyilas et al1 relating nitrogen washout measurements of lung clearance index (LCI) to spirometry in primary ciliary dyskinesia (PCD) are a welcome addition to the current debate.2–5 However, as with the data of Boon et al,4 most of their PCD patients had normal spirometry, so it would be premature to conclude that this relationship holds over the full range of severity of PCD. The suggestion that the relationship may be different in different populations of PCD patients is indeed interesting, and there is considerable genetic variability, as well as management differences across Europe.6 This could be resolved by data sharing across the large European PCD consortia such as BESTCILIA.
measurements of lung clearance index (LCI) The data of Nyilas et al1 relating nitrogen washout me... more measurements of lung clearance index (LCI) The data of Nyilas et al1 relating nitrogen washout measurements of lung clearance index (LCI) to spirometry in primary ciliary dyskinesia (PCD) are a welcome addition to the current debate.2–5 However, as with the data of Boon et al,4 most of their PCD patients had normal spirometry, so it would be premature to conclude that this relationship holds over the full range of severity of PCD. The suggestion that the relationship may be different in different populations of PCD patients is indeed interesting, and there is considerable genetic variability, as well as management differences across Europe.6 This could be resolved by data sharing across the large European PCD consortia such as BESTCILIA.
Airway diseases were initially described by nonspecific patterns of symptoms, for example “dry an... more Airway diseases were initially described by nonspecific patterns of symptoms, for example “dry and wheezy” and “wet and crackly”. The model airway disease is cystic fibrosis, which has progressed from nonspecific reactive treatments such as antibiotics for airway infection to molecular sub-endotype, proactive therapies with an unequivocal evidence base, early diagnosis, and biomarkers of treatment efficacy. Unfortunately, other airway diseases lag behind, not least because nonspecific umbrella labels such as “asthma” are considered to be diagnoses not mere descriptions.Pending the delineation of molecular sub-endotypes in other airway disease the concept of treatable traits, and consideration of airway disease in a wider context is preferable. A treatable trait is a characteristic amenable to therapy, with measurable benefits of treatment. This approach determines what pathology is actually present and treatable, rather than using umbrella labels. We determine if airway inflammation...
ABSTRACTBronchiectasis has historically been considered to be irreversible dilatation of the airw... more ABSTRACTBronchiectasis has historically been considered to be irreversible dilatation of the airways, but with modern imaging techniques it has been proposed that ‘irreversible’ be dropped from the definition. The upper limit of normal for the ratio of airway to arterial development increases with age, and a developmental perspective is essential. Bronchiectasis (and persistent bacterial bronchitis, PBB) is a descriptive term and not a diagnosis, and should be the start not the end of the patient's diagnostic journey. PBB, characterized by airway infection and neutrophilic inflammation but without significant airway dilatation may be a precursor of bronchiectasis, and there are many commonalities in the microbiology and the pathology, which are reviewed in this article. A high index of suspicion is essential, and a history of chronic wet or productive cough for more than 4–8 weeks should prompt investigation. There are numerous underlying causes of bronchiectasis, although in ma...
Chronic cough in children is common and frequently mismanaged. In the past, cough was diagnosed a... more Chronic cough in children is common and frequently mismanaged. In the past, cough was diagnosed as asthma and inappropriate asthma therapies prescribed and escalated. It has been realized that persistent bacterial bronchitis (PBB) is a common cause of wet cough and responds to oral antibiotics. The initial definition comprised a history of chronic wet cough, positive bronchoalveolar (BAL) cultures for a respiratory pathogen and response to a 2-week course of oral amoxicillin-clavulanic acid. This is now termed PBB-micro; PBB-clinical eliminates the need for BAL. PBB-extended is PBB-micro or PBB-clinical but resolution necessitating 4 weeks of antibiotics; and recurrent PBB is >3 attacks of PBB-micro or-clinical/year. However, the airway has only a limited range of responses to chronic inflammation and infection, and neutrophilic airway disease is seen in many other conditions, such as cystic fibrosis and primary ciliary dyskinesia, both chronic suppurative lung disease endotypes,...
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 2018
Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Ind... more Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Induction of the antimicrobial peptides cathelicidin (LL37) and human-beta-defensin-2 (HBD-2) may be the mechanism of any benefit. We hypothesised that antimicrobial peptide levels would be decreased, and airway infection and inflammation greater, in CF children with vitamin D deficiency. The objective of the study was to explore relationships between vitamin D, LL37 and HBD-2, and airway infection, inflammation and physiology in children with CF. Bronchoalveolar lavage (BALF) and blood were obtained from children undergoing fibreoptic bronchoscopy. Serum vitamin D, BALF HBD-2 and LL37, cultured bacteria and inflammatory markers were measured. Clinical parameters were recorded. 113 patients with CF, 23 with non-CF chronic suppurative lung disease (CSLD) and 6 healthy controls were included. We found no relationship between serum vitamin D and BALF HBD-2 or LL-37. There were no differences i...
Bronchiectasis is conventionally defined as irreversible dilatation of the bronchial tree. Bronch... more Bronchiectasis is conventionally defined as irreversible dilatation of the bronchial tree. Bronchiectasis unrelated to cystic fibrosis is an increasingly appreciated cause of chronic respiratory-related morbidity worldwide. Few randomised controlled trials provide high-level evidence for management strategies to treat the children affected by bronchiectasis. However, both decades-old and more recent studies using technological advances support the notion that prompt diagnosis and optimal management of paediatric bronchiectasis is particularly important in early childhood. Although considered to be of a non-reversible nature, mild bronchiectasis determined by radiography might be reversible at any age if treated early, and the lung function decline associated with disease progression could then be halted. Although some management strategies are extrapolated from cystic fibrosis or adult-based studies, or both, non-cystic fibrosis paediatric-specific data to help diagnose and manage t...
There is a clear need for more evidence as to how to deal with asymptomatic congenital thoracic m... more There is a clear need for more evidence as to how to deal with asymptomatic congenital thoracic malformations (CTMs), and thus the recent series from Great Ormond Street Hospital1 and the accompanying editorial2 are to be welcomed; however, the evidence review is incomplete. The risk of complications in non-operated CTMs after the postnatal period over around a decade was estimated at 3.2% …
Lung function testing in pre-school children in the clinical setting is challenging. Most cannot ... more Lung function testing in pre-school children in the clinical setting is challenging. Most cannot perform spirometry and many infant lung function tests require sedation. Lung clearance index (LCI) derived from the multiple-breath washout (MBW) test has been shown to be sensitive to early disease changes but may be time consuming and so a shortened test (LCI0.5) may be more feasible in young children. We sought to establish feasibility of MBW in unsedated pre-school children in a clinic setting and hypothesised use of LCI0.5 would increase success rates.116 pre-school children (28 healthy controls and 88 with respiratory disease), median age 4.0 years (range 2-6 years), underwent MBW tests unsedated in a clinic setting, using sulfur hexafluoride as a tracer gas and an adapted photoacoustic gas analyser.81 (70%) out of 116 children completed LCI and 72% completed LCI0.5 measurement. Test success increased significantly in patients over 3 years (0% at <2.5 years, 33% at 2.5-3 years ...
Expert review of respiratory medicine, Jan 19, 2016
Primary ciliary dyskinesia (PCD) is a rare, mostly autosomal-recessive disorder of motile cilia, ... more Primary ciliary dyskinesia (PCD) is a rare, mostly autosomal-recessive disorder of motile cilia, characterized by chronic lung disease, rhinosinusitis, hearing impairment, and subfertility. PCD is still often missed or diagnosed late since symptoms overlap with common respiratory complaints, but should be considered if one or more of the cardinal clues are present. Areas covered: We provide an overview on clinical presentations of PCD and clues for when to consider PCD, these include unexplained neonatal respiratory distress, persistent rhinitis from the first days of life, situs anomalies, or otorrhoea following tympanostomy tube insertion. Diagnosis is on the basis of clinical suspicion, and an algorithm of nasal nitric oxide, ciliary beat pattern and frequency, transmission electron microscopy, immunofluorescence of ciliary proteins and genetic studies. However, there is no one gold-standard test as yet. We reviewed the current literature based on PubMed and Ovid databases litera...
Respiratory Syncytial virus (RSV) bronchiolitis remains a hugely significant cause of morbidity a... more Respiratory Syncytial virus (RSV) bronchiolitis remains a hugely significant cause of morbidity and mortality in healthy infants [1], and is a scourge of the vulnerable, such as survivors of preterm delivery and babies with congenital heart disease. There are established guidelines for treatment [2], which in a sentence, amount to supportive measures during infection while spontaneous recovery takes place. Prevention is possible, but only with a hugely expensive and inconvenient monoclonal antibody, palivizumab, whichwill never be usedwidely in normal infants, and a vaccine seems as far away as ever. We have no specific treatments to offer, ribavirin having passed to a therapeutic graveyard, and most non-specific therapies, such as nebulized epinephrine and inhaled bronchodilators, are also ineffective. Unusually for a Cochrane review, there was a positive recommendation for the administration of nebulized hypertonic saline in acute bronchiolitis [3], but although one small trial suggests this may possibly prevent admission to hospital [4], although paradoxically without improving symptom scores, once the child is admitted, three randomised controlled trials show no vestige of benefit for this approach [5–7]. In this nihilistic context, in this issue of IJP, Modaresi et al. report a trial of nebulised magnesium in 120 children with bronchiolitis [8]. The authors are to be congratulated on carrying out a large trial in a manner that leaves no doubt as to the implications. There were large numbers enrolled so the trial was adequately powered, and the groups were well matched at baseline. The planning was a model of its kind. They selected a reasonably severe group of patients (mean saturation <90 %), in whom additional therapies would be welcome, rather than mildly affected children who would get to be expected to improve rapidly. Entirely reasonably, they did not demand positive viral studies as an entry criteria, and few would criticise this decision. Appropriately enough, the primary end-point was days in hospital, and there was no difference between the groups; thus the trial is negative, and, given its size, it is highly unlikely that a clinically significant difference was missed. There were some minor improvements in symptoms late in the course of the disease with the use of nebulised magnesium, but it is difficult to make a compelling case that these changes are sufficiently significant as to warrant bringing nebulised magnesium to the bedside. A Health Economics analysis might have been helpful, but given these changes did not translate into earlier discharge, a financial benefit seems unlikely. So in summary, an excellent job of clinical trial design and management, with a disappointing result, which, however, does not detract from the credit due to the investigators. This excellent trial also illustrates many of the problems encountered in this sort of work. The most obvious is that the group one really wants to treat are those on the verge of transfer to intensive care, to try to salvage the situation, and these babies are fortunately rare. It may still be that, despite the negative results in this trial, such babies, the tip of the iceberg, should be considered for nebulised magnesium. The other area is the unresolved question as to what is the definition of bronchiolitis, and how does acute bronchiolitis differ from a first episode of viral induced wheeze? These investigators included wheezing in their definition, and also a compatible * Andrew Bush a.bush@imperial.ac.uk
Wheezing in preschool children is very common, with a wide differential diagnosis. It is essentia... more Wheezing in preschool children is very common, with a wide differential diagnosis. It is essential to be sure of the exact sound that parents are describing; the term ‘wheeze‘ is often applied to non-specific sounds. Structural airway disease such as vascular ring should be considered. Thereafter we propose that umbrella terms for preschool wheeze should be abandoned in favour of ‘Hargreave phenotyping’, in which the presence and extent of the components of infection, inflammation, variable airflow obstruction, and fixed airflow obstruction are determined as far as is possible, rather than using a general umbrella term such as ‘asthma’. The justification for this approach is that it leads to a logical approach to treatment in the disparate airway diseases presenting in the preschool years, and should hopefully prevent over-treatment with inhaled corticosteroids. If, despite this approach, doubt remains as to the nature of the airway disease, then a therapeutic trial of treatment is ...
When a child with severe asthma (asthma defined clinically for the purposes of this review as whe... more When a child with severe asthma (asthma defined clinically for the purposes of this review as wheeze, breathlessness, and chest tightness sometimes with cough) does not respond to treatment, it is important to be sure that an alternative or additional diagnosis is not being missed. In school age children, the next step is a detailed protocolized assessment to determine the nature of the problem, whether within the airway or related to co-morbidities or social/environmental factors, in order to personalize the treatment. For example, those with refractory difficult asthma due to persistent non-adherence may benefit from using budesonide and formoterol combined in a single inhaler [single maintenance and reliever treatment (SMART)] as both a reliever and preventer. For those with steroid-resistant Type 2 airway inflammation, the use of biologicals such as omalizumab and mepolizumab should be considered, but for mepolizumab at least, there is a paucity of pediatric data. Protocols are ...
measurements of lung clearance index (LCI) The data of Nyilas et al1 relating nitrogen washout me... more measurements of lung clearance index (LCI) The data of Nyilas et al1 relating nitrogen washout measurements of lung clearance index (LCI) to spirometry in primary ciliary dyskinesia (PCD) are a welcome addition to the current debate.2–5 However, as with the data of Boon et al,4 most of their PCD patients had normal spirometry, so it would be premature to conclude that this relationship holds over the full range of severity of PCD. The suggestion that the relationship may be different in different populations of PCD patients is indeed interesting, and there is considerable genetic variability, as well as management differences across Europe.6 This could be resolved by data sharing across the large European PCD consortia such as BESTCILIA.
measurements of lung clearance index (LCI) The data of Nyilas et al1 relating nitrogen washout me... more measurements of lung clearance index (LCI) The data of Nyilas et al1 relating nitrogen washout measurements of lung clearance index (LCI) to spirometry in primary ciliary dyskinesia (PCD) are a welcome addition to the current debate.2–5 However, as with the data of Boon et al,4 most of their PCD patients had normal spirometry, so it would be premature to conclude that this relationship holds over the full range of severity of PCD. The suggestion that the relationship may be different in different populations of PCD patients is indeed interesting, and there is considerable genetic variability, as well as management differences across Europe.6 This could be resolved by data sharing across the large European PCD consortia such as BESTCILIA.
Airway diseases were initially described by nonspecific patterns of symptoms, for example “dry an... more Airway diseases were initially described by nonspecific patterns of symptoms, for example “dry and wheezy” and “wet and crackly”. The model airway disease is cystic fibrosis, which has progressed from nonspecific reactive treatments such as antibiotics for airway infection to molecular sub-endotype, proactive therapies with an unequivocal evidence base, early diagnosis, and biomarkers of treatment efficacy. Unfortunately, other airway diseases lag behind, not least because nonspecific umbrella labels such as “asthma” are considered to be diagnoses not mere descriptions.Pending the delineation of molecular sub-endotypes in other airway disease the concept of treatable traits, and consideration of airway disease in a wider context is preferable. A treatable trait is a characteristic amenable to therapy, with measurable benefits of treatment. This approach determines what pathology is actually present and treatable, rather than using umbrella labels. We determine if airway inflammation...
ABSTRACTBronchiectasis has historically been considered to be irreversible dilatation of the airw... more ABSTRACTBronchiectasis has historically been considered to be irreversible dilatation of the airways, but with modern imaging techniques it has been proposed that ‘irreversible’ be dropped from the definition. The upper limit of normal for the ratio of airway to arterial development increases with age, and a developmental perspective is essential. Bronchiectasis (and persistent bacterial bronchitis, PBB) is a descriptive term and not a diagnosis, and should be the start not the end of the patient's diagnostic journey. PBB, characterized by airway infection and neutrophilic inflammation but without significant airway dilatation may be a precursor of bronchiectasis, and there are many commonalities in the microbiology and the pathology, which are reviewed in this article. A high index of suspicion is essential, and a history of chronic wet or productive cough for more than 4–8 weeks should prompt investigation. There are numerous underlying causes of bronchiectasis, although in ma...
Chronic cough in children is common and frequently mismanaged. In the past, cough was diagnosed a... more Chronic cough in children is common and frequently mismanaged. In the past, cough was diagnosed as asthma and inappropriate asthma therapies prescribed and escalated. It has been realized that persistent bacterial bronchitis (PBB) is a common cause of wet cough and responds to oral antibiotics. The initial definition comprised a history of chronic wet cough, positive bronchoalveolar (BAL) cultures for a respiratory pathogen and response to a 2-week course of oral amoxicillin-clavulanic acid. This is now termed PBB-micro; PBB-clinical eliminates the need for BAL. PBB-extended is PBB-micro or PBB-clinical but resolution necessitating 4 weeks of antibiotics; and recurrent PBB is >3 attacks of PBB-micro or-clinical/year. However, the airway has only a limited range of responses to chronic inflammation and infection, and neutrophilic airway disease is seen in many other conditions, such as cystic fibrosis and primary ciliary dyskinesia, both chronic suppurative lung disease endotypes,...
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 2018
Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Ind... more Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Induction of the antimicrobial peptides cathelicidin (LL37) and human-beta-defensin-2 (HBD-2) may be the mechanism of any benefit. We hypothesised that antimicrobial peptide levels would be decreased, and airway infection and inflammation greater, in CF children with vitamin D deficiency. The objective of the study was to explore relationships between vitamin D, LL37 and HBD-2, and airway infection, inflammation and physiology in children with CF. Bronchoalveolar lavage (BALF) and blood were obtained from children undergoing fibreoptic bronchoscopy. Serum vitamin D, BALF HBD-2 and LL37, cultured bacteria and inflammatory markers were measured. Clinical parameters were recorded. 113 patients with CF, 23 with non-CF chronic suppurative lung disease (CSLD) and 6 healthy controls were included. We found no relationship between serum vitamin D and BALF HBD-2 or LL-37. There were no differences i...
Bronchiectasis is conventionally defined as irreversible dilatation of the bronchial tree. Bronch... more Bronchiectasis is conventionally defined as irreversible dilatation of the bronchial tree. Bronchiectasis unrelated to cystic fibrosis is an increasingly appreciated cause of chronic respiratory-related morbidity worldwide. Few randomised controlled trials provide high-level evidence for management strategies to treat the children affected by bronchiectasis. However, both decades-old and more recent studies using technological advances support the notion that prompt diagnosis and optimal management of paediatric bronchiectasis is particularly important in early childhood. Although considered to be of a non-reversible nature, mild bronchiectasis determined by radiography might be reversible at any age if treated early, and the lung function decline associated with disease progression could then be halted. Although some management strategies are extrapolated from cystic fibrosis or adult-based studies, or both, non-cystic fibrosis paediatric-specific data to help diagnose and manage t...
There is a clear need for more evidence as to how to deal with asymptomatic congenital thoracic m... more There is a clear need for more evidence as to how to deal with asymptomatic congenital thoracic malformations (CTMs), and thus the recent series from Great Ormond Street Hospital1 and the accompanying editorial2 are to be welcomed; however, the evidence review is incomplete. The risk of complications in non-operated CTMs after the postnatal period over around a decade was estimated at 3.2% …
Lung function testing in pre-school children in the clinical setting is challenging. Most cannot ... more Lung function testing in pre-school children in the clinical setting is challenging. Most cannot perform spirometry and many infant lung function tests require sedation. Lung clearance index (LCI) derived from the multiple-breath washout (MBW) test has been shown to be sensitive to early disease changes but may be time consuming and so a shortened test (LCI0.5) may be more feasible in young children. We sought to establish feasibility of MBW in unsedated pre-school children in a clinic setting and hypothesised use of LCI0.5 would increase success rates.116 pre-school children (28 healthy controls and 88 with respiratory disease), median age 4.0 years (range 2-6 years), underwent MBW tests unsedated in a clinic setting, using sulfur hexafluoride as a tracer gas and an adapted photoacoustic gas analyser.81 (70%) out of 116 children completed LCI and 72% completed LCI0.5 measurement. Test success increased significantly in patients over 3 years (0% at <2.5 years, 33% at 2.5-3 years ...
Expert review of respiratory medicine, Jan 19, 2016
Primary ciliary dyskinesia (PCD) is a rare, mostly autosomal-recessive disorder of motile cilia, ... more Primary ciliary dyskinesia (PCD) is a rare, mostly autosomal-recessive disorder of motile cilia, characterized by chronic lung disease, rhinosinusitis, hearing impairment, and subfertility. PCD is still often missed or diagnosed late since symptoms overlap with common respiratory complaints, but should be considered if one or more of the cardinal clues are present. Areas covered: We provide an overview on clinical presentations of PCD and clues for when to consider PCD, these include unexplained neonatal respiratory distress, persistent rhinitis from the first days of life, situs anomalies, or otorrhoea following tympanostomy tube insertion. Diagnosis is on the basis of clinical suspicion, and an algorithm of nasal nitric oxide, ciliary beat pattern and frequency, transmission electron microscopy, immunofluorescence of ciliary proteins and genetic studies. However, there is no one gold-standard test as yet. We reviewed the current literature based on PubMed and Ovid databases litera...
Respiratory Syncytial virus (RSV) bronchiolitis remains a hugely significant cause of morbidity a... more Respiratory Syncytial virus (RSV) bronchiolitis remains a hugely significant cause of morbidity and mortality in healthy infants [1], and is a scourge of the vulnerable, such as survivors of preterm delivery and babies with congenital heart disease. There are established guidelines for treatment [2], which in a sentence, amount to supportive measures during infection while spontaneous recovery takes place. Prevention is possible, but only with a hugely expensive and inconvenient monoclonal antibody, palivizumab, whichwill never be usedwidely in normal infants, and a vaccine seems as far away as ever. We have no specific treatments to offer, ribavirin having passed to a therapeutic graveyard, and most non-specific therapies, such as nebulized epinephrine and inhaled bronchodilators, are also ineffective. Unusually for a Cochrane review, there was a positive recommendation for the administration of nebulized hypertonic saline in acute bronchiolitis [3], but although one small trial suggests this may possibly prevent admission to hospital [4], although paradoxically without improving symptom scores, once the child is admitted, three randomised controlled trials show no vestige of benefit for this approach [5–7]. In this nihilistic context, in this issue of IJP, Modaresi et al. report a trial of nebulised magnesium in 120 children with bronchiolitis [8]. The authors are to be congratulated on carrying out a large trial in a manner that leaves no doubt as to the implications. There were large numbers enrolled so the trial was adequately powered, and the groups were well matched at baseline. The planning was a model of its kind. They selected a reasonably severe group of patients (mean saturation <90 %), in whom additional therapies would be welcome, rather than mildly affected children who would get to be expected to improve rapidly. Entirely reasonably, they did not demand positive viral studies as an entry criteria, and few would criticise this decision. Appropriately enough, the primary end-point was days in hospital, and there was no difference between the groups; thus the trial is negative, and, given its size, it is highly unlikely that a clinically significant difference was missed. There were some minor improvements in symptoms late in the course of the disease with the use of nebulised magnesium, but it is difficult to make a compelling case that these changes are sufficiently significant as to warrant bringing nebulised magnesium to the bedside. A Health Economics analysis might have been helpful, but given these changes did not translate into earlier discharge, a financial benefit seems unlikely. So in summary, an excellent job of clinical trial design and management, with a disappointing result, which, however, does not detract from the credit due to the investigators. This excellent trial also illustrates many of the problems encountered in this sort of work. The most obvious is that the group one really wants to treat are those on the verge of transfer to intensive care, to try to salvage the situation, and these babies are fortunately rare. It may still be that, despite the negative results in this trial, such babies, the tip of the iceberg, should be considered for nebulised magnesium. The other area is the unresolved question as to what is the definition of bronchiolitis, and how does acute bronchiolitis differ from a first episode of viral induced wheeze? These investigators included wheezing in their definition, and also a compatible * Andrew Bush a.bush@imperial.ac.uk
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