Oral xanthines as maintenance treatment for asthma in children.
BACKGROUND
Xanthines have been used in the treatment of asthma as a bronchodilator, though they may also have anti-inflammatory effects. The current role of xanthines in the long-term treatment of childhood asthma needs to be reassessed.


OBJECTIVE
To determine the efficacy of xanthines (e.g. theophylline) in the maintenance treatment of paediatric asthma.


METHODS
A search of the Cochrane Airways Group Specialised Register was undertaken with predefined search terms. Searches are current to May 2005.


METHODS
Randomised controlled trials,lasting at least four weeks comparing a xanthine with placebo, regular short-acting beta-agonist (SABA), inhaled corticosteroids (ICS), cromoglycate (SCG), ketotifen (KET) or leukotriene antagonist, in children with diagnosed with chronic asthma between 18 months and 18 years old.


METHODS
Two reviewers independently selected each study for inclusion in the review and extracted data. Primary outcome was percentage of symptom-free days.


RESULTS
Thirty-four studies (2734 participants) of adequate quality were included. Xanthine versus placebo (17 studies): The proportion of symptom free days was larger with xanthine compared with placebo (7.97% [95% CI 3.41, 12.53]). Rescue medication usage was lower with xanthine, with no significant difference in symptom scores or hospitalisations. FEV1 , and PEF were better with xanthine. Xanthine was associated with non - specific side-effects. Data from behavioural scores were inconclusive. Xanthine versus ICS (four studies) : Exacerbations were less frequent with ICS, but no significant difference on lung function was observed. Individual studies reported significant improvements in symptom measures in favour of steroids, and one study reported a difference in growth rate in favour of xanthine. No difference was observed for study withdrawal or tremor. Xanthine was associated with more frequent headache and nausea. Xanthine versus regular SABA (10 studies): No significant difference in symptoms, rescue medication usage and spirometry. Individual studies reported improvement in PEF with beta-agonist. Beta-agonist treatment led to fewer hospitalisations and headaches. Xanthine was associated with less tremor. Xanthine versus SCG (six studies ): No significant difference in symptoms, exacerbations and rescue medication. Sodium cromoglycate was associated with fewer gastro-intestinal side-effects than xanthine. Xanthine versus KET (one study): No statistical tests of significance between xanthine and ketotifen were reported. Xanthine + ICS versus placebo + same dose ICS (three studies) : Results were conflicting due to clinical/methodological differences, and could not be aggregated.


CONCLUSIONS
Xanthines as first-line preventer alleviate symptoms and reduce requirement for rescue medication in children with mild to moderate asthma. When compared with ICS they were less effective in preventing exacerbations. Xanthines had similar efficacy as single preventative agent compared with regular SABA and SCG. Evidence on AEs (adverse effects) was equivocal: there was evidence for increased AEs overall, but no evidence that any specific AE (including effects on behaviour and attention) occurred more frequently than with placebo. There is insufficient evidence from available studies to make firm conclusions about the effectiveness of xanthines as add-on preventative treatment to ICS, and there are no published paediatric studies comparing xanthines with alternatives in this role. Our data suggest that xanthines are only suitable as first-line preventative asthma therapy in children when ICS are not available. They may have a role as add-on therapy in more severe asthma not controlled by ICS, but further studies are needed to examine this, and to define the risk-benefit ratio compared with other agents.
Seddon
P
P
Royal Alexandra Hospital for Sick Children, Dyke Road, Brighton, Sussex, UK, BN1 3JN. freya.seddon@tesco.net
Bara
A
A
Ducharme
F M
FM
Lasserson
T J
TJ
D000628:Aminophylline / Q000627:therapeutic use; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000627:therapeutic use; D002648:Child; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D013806:Theophylline / Q000627:therapeutic use; D014970:Xanthines / Q000627:therapeutic use*
D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D014970:Xanthines; D000628:Aminophylline; D013806:Theophylline