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Department of Pediatrics and Postgraduate Institute, Medical Sciences School, Lucas Machado Foundation, BrazilCampos Sales Pediatric Pulmonology Outpatient Referral Clinic, Belo Horizonte Municipal Public Health Authority, Brazil
Corresponding author. Department of Pediatrics, Medical School, Federal University of Minas Gerais, Avenida Alfredo Balena, 190/Room 267, 30130-100 Belo Horizonte, Brazil. Tel.: +55 31 34099772; fax: +55 31 34099664.
Universidade Federal de São João del-Rei, BrazilPediatric Pulmonology Unit, University Hospital, Federal University of Minas Gerais, Brazil
There are only a few studies assessing the relationship between adherence rate to ICS, as assessed by electronic monitoring, and the level of asthma control in childhood. The present study was carried out to examine the relationship between adherence to beclomethasone diproprionate (BDP) as well as other factors related to poor asthma control. In this prospective cohort study, 102 steroid naïve randomly selected subjects with persistent asthma, aged 5–14 years were prescribed 500–750 μg daily of BDP-CFC and followed during one year. Adherence to BDP was measured electronically in the 4th, 8th and 12th months of study. The level of asthma control was classified as either controlled or uncontrolled instead of the current three categories recommended by the Global Initiative for Asthma (GINA). Mean adherence rate was higher in patients with controlled asthma during follow-up, but went down from 60.4% in the 4th month to 49.8% in the 12th month (p = 0.038). Conversely, among patients with uncontrolled asthma, the mean adherence rate decreased from 43.8% to 31.2% (p = 0.001). Multivariate analysis showed that the level of asthma control was independently associated to the adherence rate in all follow-up visits (p-values equal or lower than 0.005). The level of asthma control was directly proportional to adherence rate. Our results suggest that a BDP daily dose by 300 μg seems to be enough to attain control over mild and moderate persistent asthma, including exercise induced asthma.
For instance, Milgrom et al. demonstrated that mean adherence to ICS therapy – measured through electronic monitoring – of children requiring a prednisone burst was 13%, compared to 68% adherence for children without severe exacerbations.
Recent versions of international guidelines have focused on asthma control, through the following major components: frequency of patient symptoms (daytime and nighttime, including nighttime awakening), interference with normal activity, frequency of exacerbations and short-acting beta2-agonist use, and lung function. Accordingly, asthma should be considered controlled when these abnormalities are absent; partly controlled when at least one is present in at least a week; and uncontrolled asthma when three or more are present in a least a week.
However, in a chronic disease like asthma, some degree of suboptimal adherence can be tolerated within certain limits. The estimate of this acceptable level of non-compliance that can still keep the disease under control is of great interest to real-life strategies.
The present study was carried out to assess the relationship between the adherence rate to beclomethasone dipropionate (BDP) – assessed through an electronic monitor – and the level of asthma control as well as other factors related to poor asthma control. Works on this subject in pediatric patients are still scarce.
Study design, duration and setting
This is an ambulatory-based prospective randomized cohort study, spanning 12 months, where only patients with persistent uncontrolled and untreated asthma were admitted. They were treated and followed at the Campos Sales Outpatient Referral Clinic, linked to the Belo Horizonte Municipal Public Health Authority (BHMPHA) network. According to the protocol standardized by the BHMPHA, the participants received beclomethasone diproprionate (BDP)-CFC, the cheapest ICS available in Brazil, free of charge (Clenil®, Chiesi Brazil, 250 μg/puff, 200 actuations/canister) and a pear-shaped plastic valved spacer (Flumax®, Flumax Medical Equipments, Brazil). A pressure-actuated electronic monitor attached to the BDP-metered-dose inhaler (Doser CT®, Meditrack Products, USA) was also given for use throughout the 12-month follow-up. It is important to note that formulations containing 100 and 200 μg of BDP are not commercialized in Brazil.
Levels of asthma control and follow-up
As the main goal of asthma treatment is to achieve a normal or near normal life, or, in other words, achieve complete asthma control, only two categories were adopted in the follow-up visits: controlled and uncontrolled asthma. The two categories represent, respectively, the definitions of controlled asthma on one hand, and on the other, partially controlled and uncontrolled asthma according to GINA classification.
Thus, controlled or uncontrolled asthma were pre-defined as (1) absence or presence of daytime symptoms, limitations of activities, nocturnal symptoms/awakening, need for reliever/rescue treatment, and/or exacerbations in the four weeks preceding the scheduled follow-up visits for the 4th, 8th and 12th months and/or (2) FEV1 equal or higher than and lower than 80% of the predicted values. The forced expiratory spirometry was performed within two weeks of the follow-up visits in those able to perform the maneuver, respectively.
Inclusion and exclusion criteria
We admitted children and adolescents aged 5–14 years, with persistent uncontrolled asthma, whose parents or legal guardians were able to read and write. Exclusion criteria were intermittent asthma, previous use of ICS or other anti-asthma medication in the four months prior to the study, and other chronic and/or systemic concurrent disease.
Only albuterol-pMDI (provided for quick relief of symptoms as needed), and BDP-CFC-pMDI (250 μg/puff, as controller medication) were given for free by the BHMPHA. One puff of BDP was prescribed twice (i.e. 500 μg/day, 1 puff at morning and at bedtime) or three times daily (i.e. 750 μg/day, 1 puff at morning and two puffs at bedtime) just after protocol admission depending on asthma severity, as follows: mild–moderate and severe persistent, respectively.
For patients receiving 500 μg/day and 750 μg/day a stepping up strategy of, respectively, 750 μg/day and 1000 μg/day were pre-defined as long as optimal adherence rate was verified and asthma control was not achieved with the initial doses. That simplified and adapted therapeutic regimen was adopted because of all participants were from very low income families and for that reason they could not afford either ICS in a single inhaler or ICS and long acting beta-agonists combinations. Patients and/or their caregivers taught and retaught inhaler/spacer technique in every follow-up visit.
Adherence rate assessment
Cumulative adherence rates verified in the first 4 months after enrollment, between 4 and 8 months and between 8 and 12 months were recorded through Doser CT® (MedTrack Products, USA). Doser CTs were collected at 30–60 day intervals. One Doser CT® per month was dispensed free of charge to each subject at every follow-up visit, and were asked to return them every two months.
Adherence rates were calculated according to the following formula: number of puffs used/numbers of puffs prescribed × 100.
Descriptive statistics were used to report the baseline characteristics of the studied population. The mean adherence rate to BDP was plotted against the level of asthma control by box-plot for the adherence with Doser CT® in the 4th, 8th and 12th month and respective mean (±standard deviations), median, range (minimum to maximum) and 1st and 3rd quartiles distributions. Comparison of asthma control level was done using Student’s t and Mann–Whitney’s tests.
The predictive independent variables in the logistic model were incorporated only for variables whose p-values were ≤0.25 in the univariate analysis. Each non-significant variable was excluded through stepwise strategy and a significance level of 5% was used to ensure a variable remained in the final model. Final model appropriateness was assessed by Hosmer–Lemeshow test.
we assumed that the mean adherence rate to achieve controlled asthma should be at least 45%, (with SD equal to 15%) whereas an adherence of 35% (with the same SD) would lead to a partly controlled/uncontrolled asthma (mean difference of 10%). Assuming an alpha and beta error of 0.05 and 0.20 (80% power), respectively, a minimum of 36 patients in both categories were necessary for statistical analysis. Taking into account a dropout rate of 50%, a total of 108 patients should be recruited.
The study protocol and informed consent were approved by the Committee of Ethics in Research of the Universidade Federal de Minas Gerais.
A hundred and two patients were recruited for the study. Their baseline characteristics are displayed in Table 1.
Table 1Baseline characteristics of the participants (N = 102).
Age group (years)
More than 6
Mother’s schooling level (years)
Up to 8
More than 9
Father’s schooling level (years)
Up to 8
More than 9
Mean family monthly income (US$)
Up to 100
More than 100
Duration of asthma (years)
Up to 3
More than 4
Previous non-scheduled emergency department visits
Previous hospitalizations due to acute asthma
BDP-CFC dosage after admission (μg/daily) on the study protocol
There was a predominance of male patients (58.8%), aged up to six years (52.0%), whose parents completed elementary education (65.7% and 65.4% respectively). Their monthly family income were lower than US$100 (56.4%), demonstrating that they can’t afford any anti-asthmatic drug. As to the clinical characteristics, there is a greater frequency of patients with asthma for less than 3 years (55.0%), with at least one visit to emergency services (88.2%) and one hospitalization (44.8%) before protocol admission. Only 7 (6.9%) received 750 μg daily of BDP after admission on the study protocol.
Forty-three out of the 102 studied patients (42.1%) were able to perform forced expiratory maneuver. For the remaining 59 subjects the level of asthma control was based on clinical grounds.
Table 2 shows the distribution of the level of asthma control according to the adherence rate measured during the three follow-up visits.
Table 2Adherence rate (%) stratified by level of asthma control in the 4th, 8th, and 12th month (N = 102).
It is important to note that the minimum of 36 patients (see sample size assumptions) in each category, i.e. controlled and uncontrolled, was effectively reached in the 8th (42 and 60) and the 12th (64 and 38) month, respectively.
From the baseline, the proportion of controlled asthma increased progressively to 17.6%, 41.2% and 62.7%, whereas the frequency distribution of uncontrolled asthma decreased from 100% at admission (see inclusion criteria) to 82.4%, 58.8% and 37.3% in the 4th, 8th and 12th month, respectively (data not shown).
There were higher values for both the mean and the median adherence rate in patients with controlled asthma in the 4th, 8th, and 12th month of follow-up. Among them the mean adherence rate was reduced from 60.4% (on the 4th month) to 49.8% (on the 12th month, p-value = 0.038), whereas among patients with uncontrolled asthma, the mean adherence rate reduced from 43.8% (on the 4th month) to 31.2% (on the 12th month, p = 0.001). As the majority of the participants were prescribed 500 μg as an average daily dose, they gained asthma control with approximately 270 μg (54% out of 500 μg) and 235 μg (47.0% out of 500 μg) in the 4th and 12th month respectively. Conversely, daily doses lower than 219 μg (43.8% out of 500 μg) on the 4th and 156 μg (31.2% out of 500 μg) on the 12th month were insufficient to achieve asthma control.
Analysis of the evolution of FEV1 results among the 43 patients who were able to perform forced expiratory maneuver has consistently pointed to the same direction of symptomatology, i.e., FEV1 from 81.8% to 90.6% of the predicted were achieved with adherence rate from 42.9% to 46.7% in each of the three follow-up visits (data not shown).
On the other hand, to attain both, functional and clinical control, including exercise induced asthma, there was not necessarily a mean adherence rate increase in the same proportion because the rate dropped from 60.4% to 49.8% (p = 0.038). This apparent paradox can be better understood in Fig. 1, where we have plotted the median adherence rate to BDP against the levels of asthma control (controlled or uncontrolled) at each follow-up visit.
The box-plot shows a consistent, dose-response gradient for the adherence rate and the level of asthma control in the three moments of the clinical-functional assessment. In other words, the level of control is always better in patients with higher adherence rate (p ≤ 0.001). Our results suggest that the clinical and/or functional control of mild to moderate persistent asthma might be possible with at least 45–60% adherence rate to the adopted BDP-CFC therapeutic regimens, i.e., 225 μg (45% out of 500 μg) to 300 μg (60% out of 500 μg) daily.
Table 3 shows the results of the final multivariate analysis model, which should be interpreted alongside the data from the mean adherence rates for each step in the two categories of asthma control, as shown in Fig. 1A–C.
Table 3Multivariate analysis final model at the time of each follow-up visit.
Multivariate analysis showed that the level of asthma control was consistently and independently related to the adherence rate in all three visits (p-values equal or lower than 0.005). There was also a trend toward statistical significance between controlled/uncontrolled asthma and mother’s schooling level in the 8th month of follow-up. There was no association with other co-variables, i.e., sex, age group, parents’ schooling level, asthma duration, asthma severity, previous emergency room visits and hospitalization before protocol admission.
To the best of our knowledge, this is the first prospective randomized medium term study that assessed the relationship between level of asthma control and adherence rate to BDP, measured exclusively through an electronic monitor in children and adolescents. This is the main clinical importance and novelty of our findings. However, the lack of similar studies, unfortunately, hinders more detailed comparisons with our results.
In clinical practice, if an optimal level of asthma control is not achieved, the adherence rate to anti-asthmatic drugs, among other factors, must be checked before prescribing a higher dose of inhaled steroids, combined or not with an add-on medication.
Electronic monitors attached to pMDIs are the most reliable method for assessing adherence to ICS.
The few studies in which electronic monitors were used to track adherence to ICS have always shown lower adherence rates than those reported by the patient and family, pharmacy records and canister weight.
Even though there is not an ideal way to measure ICS adherence, this method is considered the most accurate, the exception being times when the patient might deliberately actuate the pMDI without actually inhaling the medication.
As demonstrated by others, an adherence rate to ICS by 40%–50% was enough to obtain asthma control.
In a meta-analysis of 10 works recruiting pediatric patients carried out by Bender et al., one of the studies, with a follow-up of only three months, subjects who experienced exacerbations had a median ICS adherence rate of 14%, whereas those with controlled asthma had a median adherence rate of 68%.
The authors point out that the wide-ranging disparity in adherence emphasizes the need to use more reliable measures to distinguish between patients who adhere to the therapeutic regimen and those who do not, both in clinical practice and in research.
Even though they had different aims, Pedersen et al. in one of the few studies with children, reported results in the same direction as ours. They followed 19 children, aged 6–15 years with moderate and severe asthma, taking budesonide for four weeks. The use of half (i.e. 100 μg/day of budesonide) of the prescribed dose – verified by canister weight – was sufficient to control their symptoms. The authors concluded that low doses of budesonide – which have a similar anti-inflammatory effect than BDP, had a marked anti-asthma efficacy in children.
Our work has some clinical implications. Firstly, both adherence rate to ICS and level of asthma control must be systematically checked in scheduled and non-scheduled appointments. Secondly, our results suggest that to attain asthma control in children and adolescents, the adherence rate can in fact be lower than the ideal 100%, since in our prospective medium term cohort study, a minimum of 60% adherence to the adopted BDP regimen (i.e., by 300 μg daily) was enough to achieve asthma control, as defined by symptoms – including exercise induced asthma – and lung function. It is important to stress that in our patients the adherence rate needed to obtain FEV1 superior to 80–90% of predicted values was approximately the same (45%–60%) needed to attain symptom control.
This work was supported by Belo Horizonte Municipal Public Health Authority and Universidade Federal de Minas Gerais (UFMG), Brazil.
P. Camargos is supported by the Brazilian research agencies CNPq – Conselho Nacional de Desenvolvimento Científico e Tecnológico (Grant 303827/2009-2), and FAPEMIG – Fundação de Amparo à Pesquisa do Estado de Minas Gerais (Grant PPM-00230-10). These research agencies had no influence in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Conflicts of interest
The authors declare no conflict of interest.
Measuring adherence to asthma medication regimens.