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Three Part Question

In [children with mild to moderate persistent asthma] does [once daily and twice daily administration of inhaled steroids] have [the same efficacy]?

Clinical Scenario

A six year old girl comes to your outpatient pediatric clinic with a two-month history of cough and shortness of breath, requiring, nearly three times a week, administration of beta 2 agonists by jet-nebulizer. She has often been noticed to wheeze at school during the gymnastic class and when she's laughing or crying; almost once a week she awakes during the night complaining of cough and respiratory difficulties.
Your diagnosis is persistent asthma (1) and after a short course of nebulized salbutamol (albuterol) and oral steroids you decide to start, twice a day, a prophylaxis with inhaled steroids, via a spacer device. As her mother is working outside home till late afternoon, she asks you if a once-daily administration would have the same efficacy.

Search Strategy

Medline 1966-12/01 using OVID interface, Cochrane Library (2001), PubMed clinical queries.
"Inhaled steroids" OR glucocorticoids OR glucocorticosteroids OR budesonide OR mometasone OR flunisolide OR fluticasone propionate OR beclomethasone dipropionate AND ( once versus twice OR once with twice daily OR OD OR BID administration ) AND asthma. Limits: All Children:0-18 years, Randomized Controlled Trial.

Search Outcome

No systematic reviews. 31 studies found, 9 were relevant. (Papers available in abstracts only and studies including both adults and children aged > 12 were excluded).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Campbell LM et al, 1998, UK	167 children, age 5-12 yrs with symptomatic asthma, multicenter study O OD vs BID Budesonide by Dry Powder for 8 wks	Double blind RCT (level 1b) Jadad score: 2	Peak Expiratory Flow(PEF), Forced Expired volume in 1 second (FEV1), Forced Vital Capacity (FVC), well-being and symptom score, albuterol use, adverse events	OD >BID for evening PEF:+19.7 l/min vs + 8.3 l/min (p=0.013), no other significant differences (morning PEF: +24.6 l/min vs +15.2 l/min, p=0.059)	Ten patients excluded from the all-patients-treated population A greater number of patients randomised to the BID arm: 90 vs 77 Patients compliance not assessed
Jonasson G et al, 1998, Norway	163 children, age 7-16 yrs , with mild asthma, outpatient clinic OD vs BID Budesonide by Dry Powder for 12 wks	Double blind RCT (level 1b) Jadad score: 3	PEF, FEV1, FVC,symptom score, beta agonist use, metacoline challenge, exercise test,adverse events	No significant differences between OD vs BID Budesonide:FEV1% -0.05 (95% CI –3.3 to +3.0); PEF 2.9 L/min (95% CI –10.8 to +16.6)	Patients with near-normal lung function: FEV1 at baseline >100%, reversibility of 3%
Heuck C et al, 1998, Denmark	24 children, age 5.6-12.5 yrs, with mild asthma,outpatient clinic OD vs BID Budesonide by Metered Dose Inhaler + spacer crossover trial, 2 treatment periods of 4 wks.	Double blind RCT (level 1b) Jadad score: 3	Lower leg growth, PEF, symptom score, albuterol use, markers of collagen turnover	Significant reduction of lower leg growth rate (p=.04) and markers of collagen turnover with BID. No other significant differences between OD and BID:Morning PEF (95% CI – 4 to+15 L/min ), in evening PEF(95% CI –3 to +16 L/min)	Small study The trial did not include a placebo period
Moller C et al, 1999, Sweden	206 children, age 5-15 yrs, with stable asthma, multicenter study OD vs BID Budesonide by Dry Powder for 12 wks	Double blind RCT (level 1b) Jadad score: 3	FEV1, FVC, Forced expiratory flow between 25 and 75% of Forced Vital Capacity (FEF 25-75), PEF, symptom score, albuterol use, adverse events	No significant differences between OD and BID: Morning PEF –2.8 L/min (90% CI –10.4 to + 4.5); Absolute Reduction for FEV1% –0.08 (95% CI –3.4 to + 0.9)	Difference in patients demographic characteristics (duration of asthma in months) between OD and BID
Baker JW et al, 1999, USA	480 children, age 6 months-8 yrs, with moderate persistent asthma, multicenter study. Budesonide inhalation suspension by jet nebulizer :0.25 mg OD vs. 0.25 mg BID vs. 0,50 mg BID vs.1 mg OD vs. Placebo for 12 wks	Double blind RCT (level 1b) Jadad score: 2	FEV1, PEF, symptom score, adverse events and in a subgroup cortisol testing	Improvement in FEV1 significant between Budesonide 0.50 mg BID and placebo (0.17 / 0.04 L/min), but not significant between Budesonide 0.1 mg OD and placebo (0.11/0.04 L/min). For the other outcomes: 0,50 mg BID >1 mg OD, but not significant	Lost to follow-up: 27% Differences in % patients using inhaled steroids before entering into the study between OD and BID groups
Jonasson G et al, 2000, Norway	122 children, age 7-16 yrs, with mild asthma, outpatient clinic OD vs BID Budesonide by Dry Powder for 27 wks	Double blind RCT (level 1b) Jadad score: 3	FEV1, FEF 25-75, PEF, exercise test, metacoline challenge, symptom score, growth rate, eosinophil count, compliance	No significant differences between BID and OD	Compliance declined rapidly
LaForce CF et al, 2000, USA	242 children, age 4-11 yrs, with persistent stable asthma, multicenter study OD vs BID Fluticasone propionate by Dry Powder for 12 wks	Double blind RCT (level 1b) Jadad score: 3	FEV1, PEF symptom score, nightime awakening, albuterol use, adverse events	BID > OD for FEV1 change in % (95% CI –11.28 to –0.124); no other significant differences: for morning PEF (95% CI –27.26 to + 9.26)	Asthma had to remain stable for all the study period; high rate of discontinuation in the placebo group
Purucker et al, 2003, USA	262 children, age 4-11 yrs, with persistent stable asthma, single study Fluticasone propionate by Dry Powder 0,05 mg OD vs 0.1 mg BID vs placebo X 12 wks	Double blind RCT (level 1b) Jadad score: 2	FEV1, PEF symptom score, nightime awakening, albuterol use	Change in FEV1 in L/min from baseline : OD fluticasone 0.08 (NS), BID fluticasone 0.13 (NS) and placebo 0.05 (NS). BID Fluticasone vs. Placebo: Absolute Reduction for morning PEFR in L/min 27.8 (p<.050)). OD Fluticasone vs. Placebo: Absolute Reduction for morning PEFR in L/min 15.3 L/min (NS)	Lost to follow-up:35%. No details about how randomisation was performed and about demographic characteristics of the three groups.
Purucker et al, 2003, USA	242 children, age 4-11 yrs, with persistent (more severe than that of Study FLTA 2007) stable asthma. Single study. Fluticasone propionate by Dry Powder 0.1 mg OD vs 0.2 mg BID vs placebo X 12 wks	Double blind RCT (level 1b) Jadad score: 2	FEV1, PEF symptom score, nightime awakening, albuterol use	BID Fluticasone vs. Placebo: Absolute Reduction for FEV1 in L/min 0.27 (p< .001). 100 micrograms OD Fluticasone vs. Placebo: Absolute Reduction for FEV1 in L/min 0.16 (p<.001). No significant difference between the two FP arms. BID Fluticasone vs. Placebo: Absolute Reduction for morning PEFR in L/min 22.8 (p<.050)). 100 micrograms OD Fluticasone vs. Placebo: Absolute Reduction for morning PEFR in l/min 13.3 l/min (NS)	Lost to follow-up:45%. No details about how randomisation was performed and about demographic characteristics of the three groups.

Comment(s)

As Baker's study evaluate the efficacy of different doses of Budesonide (4 Groups) compared to placebo, 8 studies were found that specifically compare the once-daily vs twice-daily administration of inhaled steroids. Overall the methodological quality of the included studies was not always satisfactory: even if the majority of the references mentioned the number of patients excluded from the study, withdrawals and drop-outs were described and commented only in Heuck's and in Moller's articles; in Baker's and in both Purucker's studies "lost to follow-up" was > 20%. Intention to treat analysis was reported to be used by Jonasson, by LaForce and by Purucker; allocation concealment was unclear in most of the cases and often details of methods used to generate the random allocation sequence were lacking. This overview found a heterogenous group of trials with different results; although the majority of studies reported not significant difference between the two regimens the overall findings of the seven studies are not sufficient to support the evidence that administering inhaled steroids once-daily and twice –daily has the same efficacy.

Clinical Bottom Line

In mild to moderate persistent asthma, in children, inhaled steroids should continue to be given twice-daily. Once daily administration might have a similar efficacy at least in some subgroups of patients with more stable asthma, but further well conducted randomized controlled studies are needed.

References

1. Campbell LM, Bodalia B, Gogbashian CA, et al. Once-daily budesonide:400 ugr once daily is as effective as 200 ugr twice daily in controlling childhood asthma. Int J Clin Pract 1998;52(4):213-219.
2. Jonasson G, Carlsen KH, Blomqvist P. Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids. Eur Respir J 1998;12(5):1099-1104.
3. Heuck C, Wolthers OD, Kollerup G, et al. Adverse effect of inhaled budesonide (800 μgr) on growth and collagen turnover in children with asthma: a double-blind comparison of once-daily versus twice-daily administration. Journal of Pediatrics 1998;133(5):608-612.
4. Moller C, Stromberg L, Oldaeus G, et al. Efficacy of once-daily versus twice-daily administration of budesonide by turbuhaler in children with stable asthma. Pediatric Pulmonology 1999;28(5):337-343.
5. Baker JW, Mellon M, Wald J, et al. A multiple–dosing, placebo–controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999;103(2):414-21.
6. Jonasson G, Carlsen KH, Jonasson C, et al. Low-dose inhaled budesonide once or twice daily for 27 months in children with mild asthma. Allergy 2000;55(8):740-8.
7. LaForce CF, Pearlman DS, Ruff ME, et al. Efficacy and safety of dry powder fluticasone propionate in children with persistent asthma. Ann Allergy Asthma Immunol 2000;85(5):407-415.
8. Warner JO, Naspitz CK, Cropp GJA. Third International Pediatric Consensus Statement on the management of childhood asthma. Pediatr Pulmonol 1998;25(1):1-17.
9. Purucker ME, Rosebraugh CJ, Zhou F, Meyer RJ. Inhaled fluticasone propionate by Diskus in the treatment of asthma. A comparison of the efficacy of the same nomimal dose given either once or twice a day. Study FLTA 2007. Chest 2003;124(4):1584-1593.
10. Purucker ME, Rosebraugh CJ, Zhou F, Meyer RJ. Inhaled fluticasone propionate by Diskus in the treatment of asthma. A comparison of the efficacy of the same nomimal dose given either once or twice a day. Study FLTA 2008. Chest 2003;124(4):1584-1593.