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Treatment regimen for families of children with cystic fibrosis (CF) is considerable, particularly when nebulised therapies for chronic Pseudomonas aeruginosa airway infection are prescribed. Adherence to these regimens is variable, particularly in adolescence. Previously, we reported children to be more adherent in evenings compared to mornings, suggesting an association with time-pressure. The aim of this study was to determine whether adherence would be better in adolescent patients at weekends and during school holidays when time-pressures may be less.
Study design
24 patients (14 male, median [range] age 13.9 [11.1–16.8] years) were enrolled from two regional paediatric CF centres in the United Kingdom. Data for a full scholastic year, were downloaded openly from a breath-activated data logging nebuliser (I-neb™). Adherence (% of doses taken÷expected number) was calculated during term-times, holidays, weekends and weekdays, for each patient.
Results
Large variations in adherence were seen between patients. However, adherence during term-time was significantly better than holidays (p<0.001). Weekday adherence was better than weekend adherence in term-time but not holidays. Interestingly, patients prescribed three daily treatments took on average 1.4 treatments/day, a similar number to those prescribed two daily treatments.
Conclusion
Overall adherence to inhaled therapies was reasonable, but significantly reduced during holiday periods. This suggests a need for families to have not only time, but also structure in their daily routine to maintain optimal adherence to long-term therapies. It is important for CF teams to appreciate these factors when supporting families.
Families of children with cystic fibrosis (CF) face a considerable treatment burden, which is compounded by nebulised treatments for chronic Pseudomonas aeruginosa airway infection [
]. While it is known that adherence to all forms of treatment is an issue in any chronic disease, and particularly so during adolescence, very few studies have examined actual rates of adherence in this age group. This is partly because, until relatively recently, accurately measuring adherence to therapies was difficult.
The development of breath-actuated nebuliser devices incorporating built-in data-logging systems has provided a highly reliable mechanism for accurately recording and assessing adherence [
]. Using this technology, we have previously shown that adherence to inhalation therapies is often poor but that children of all ages are generally more adherent to therapy in the evenings than in the mornings [
]. This suggested that time-pressures in the mornings might adversely affect adherence and thus we speculated whether adherence would be better when time-pressures may be less [
]. Consequently, the present study explored this further by examining weekday/weekend and term-time/holiday adherence data in a group of adolescents with CF over a full, UK scholastic year.
2. Methods
2.1 Study design
In this observational study, adherence to nebulised therapies during weekdays/weekends and term-time/holidays in young people attending secondary school was calculated based on data collected and analysed retrospectively during routine clinical practice over a full, UK, scholastic year.
2.2 Participants
Participants attended one of two regional paediatric CF clinics; Alder Hey Children's Hospital in Liverpool or Leeds General Infirmary. All patients with CF, aged between 11 and 17 years at or starting secondary school in September 2008, who were established on therapy through the I-neb™ (Respironics, Philips, Chichester, UK) using standard tidal breathing mode of inhalation, were included in the study. Patient demographics and clinical characteristics including pulmonary function tests were recorded.
2.3 Ethics
Clarification regarding the nature of the study was sought from the Alder Hey Research, Development and Ethics Users Views Group. Following methodological review, the opinion of this committee was that this study constituted service evaluation. All families were aware that nebuliser usage and adherence to treatment were being monitored routinely.
2.4 Device, drug delivery, monitoring and measurements
The I-neb™ adaptive aerosol delivery device has a data-logging facility which records the dates and times of treatments. Patients and their parents are encouraged to bring their handheld devices to clinic appointments and on average, bring them to half their clinic appointments. At clinic, the data-log is accessed via a reading cradle using dedicated computer software provided by the manufacturer. The data are discussed routinely with the individual patient and their family during the clinic visit. The I-neb has sufficient memory to record 5000 events allowing adherence to be calculated retrospectively if clinic appointments were missed or the device forgotten.
Over a full UK scholastic year, the number and date of all treatments were recorded, data routinely collected in both centres as part of service evaluation. Adherence was calculated as the percentage of the number of taken treatments/number of prescribed treatments. This information combined with the dates of school holidays for all patients in the two clinics allowed adherence to be calculated for weekdays and weekends, and term-times and holidays over the year. Overall and individual holiday adherence rates were calculated to investigate whether individuals and their families experienced difficulties over particular vacation periods. This included ‘half-term’ breaks, which are normally week-long holidays mid-way through a school-term. Children from both centres spent on average 38 weeks (73%) of the year at school.
2.5 Treatments
Participants were prescribed a range of inhalation therapies (Colistin, Tobramycin and Dornase alfa but not hypertonic saline) with varying frequencies (1–3/day) during the study period. For patients taking Colistin, a commercial preparation was used (Promixin®, Profile Pharma Ltd., Chichester, UK), with the treatment dose being 1 mega unit (MU) diluted in either normal saline or sterile water and given either once or twice daily.
2.6 Statistics
Data were analysed and presented depending on whether they were normally distributed or not. Thus, adherence was expressed as mean (standard deviation [SD]) with differences for individual patients examined between different time points using a paired samples t test. Data were displayed graphically as mean (standard error of the mean [SEM]) or as line graphs. We used SPSS 18.0 and all statistical tests were two-tailed with a p value equal to or less than 0.05 considered statistically significant.
3. Results
3.1 Participants
Data from 24 patients (12 Liverpool; 12 Leeds) between 1st August 2008 to the 31st July 2009, were included in this study. Median (range) age was 13.9 (11.1–16.8) years and median (range) FEV1 and FVC, 78 (43–105)% and 88 (52–110)% respectively.
Patients were prescribed one treatment (n=10), two treatments (n=5) or three treatments (n=9) every day. In two patients, treatment regimens were changed very soon after the start of the study from three to one treatment/day and so they were analysed as taking one treatment each day. Between the two centres, 7 different combinations of nebulised treatment were prescribed i.e. once daily colistin, or twice-daily colistin and once daily DNAse etc. Overall, 16 patients were prescribed Colistin, 13 patients DNAse and 3 patients Tobramycin. Over the study period, according to the Leeds criteria for P. aeruginosa infection [
], 8 patients were free of infection, 8 patients were intermittently infected and 10 patients were chronically infected. The median (range) duration of use of the I-neb prior to the study period was 20 (1–36) months. The mean (SD) percentage of treatments taken, which were successfully completed was 92 (14)% during term-time and 92 (15) during the holidays.
3.2 Adherence
Mean (SD) overall adherence over the 12 months of treatment through the I-neb was 65 (28)% with 12/24 patients achieving an overall adherence of over 75%. No difference in adherence was observed between the two CF centres.
When paired overall adherence for weekdays and weekends was analysed (Fig. 1a ), mean (SD) weekday adherence was significantly greater than that at weekends (weekday, 67 (28)%; weekend, 60 (29)%: p=0.001). All but 3/24 patients had better adherence on weekdays than weekends (median (range) difference in adherence 5 (−5 to 34)%).
Fig. 1Comparison of adherence to treatment for individual patients during a) weekdays and weekends and b) holidays and term-times. The horizontal thickened bars represent mean adherence for the group (*p<0.001).
Mean (SD) term-time adherence was greater than holiday adherence (term-time, 66 (28)%; holiday, 51 (29)%: p<0.001) (Fig. 1b). Adherence for 20/24 patients was better during term-time and in seven patients, by greater than 10%.
When adherence to treatment for patients over term-time and holiday periods was examined, large variations were apparent both between and within individual patients (median (range) coefficient of variation, 19(3–103)%). Overall, there were no significant differences in adherence during particular holiday periods, although there was a trend for adherence over Christmas to be worst (Table 1a). This trend was most apparent for patients prescribed three nebulised treatments a day (Fig. 2).
Table 1aAdherence during specific holiday periods.
Patients prescribed one daily nebulised treatment took on average 0.8 treatments/day over the course of the year (median (IQR) annual number of treatments, 284(169)). Patients prescribed two or three treatments a day, took on average 1.4 treatments/day (median (IQR) annual number of treatments: two/day, 502 (287); three/day, 516 (611)).
When adherence for both weekday/weekends and term-times/holidays was combined and analysed, patients were found to be most adherent to their treatments during term-time weekdays and least adherent during holiday weekends (Table 1b).
Table 1bComparison of weekend and weekday adherence during both term-time and holidays.
This is the first study that we know of to investigate rates of treatment adherence at weekends and during the holidays. In adolescents with CF, we have shown that adherence is best on weekdays during term-times, and worst on weekends during holidays. We have also shown a pattern for adherence to be worst in those patients taking three treatments/day particularly over Christmas holidays, with no difference in the number of treatments taken over a year by those prescribed two or three treatments daily.
Given our previous work demonstrating that adherence is generally better in the evenings [
], our expectation had been that families would find more time to devote to challenging therapies during the school holidays and at weekends. However, the reverse was actually true with adherence being better on weekdays than weekends, and term-times than holidays. These results potentially reflect the importance of CF care being integrated into structured, daily family schedules, which act to contain treatments. Such routines tend to be inherent to schooldays, and it is this factor that is more likely than unlikely to explain the present findings. However, other factors may also impact. Some families may take breaks/holidays away from the home environment over these periods and for a variety of practical and/or psychological reasons, actively decide to take ‘treatment holidays’ rather than take medication and equipment away with them. Our previous premise—that adherence to complex therapies was better in the evenings because more time was available for complex treatments, may have only been partly true [
]. The lack of time on school-day or weekend mornings may have been just as important, particularly in busy households where parents attempt to get adolescents to school on time, or simply out of bed. It is worth emphasising that the disparity between weekday/weekend and holiday/term-time adherence appears to be most apparent in those children with overall poor adherence. Generally, adherence in adolescents who take their medication more than 90% of the time does not appear to drop significantly during weekends and holidays (data not presented).
Patients took a similar number of nebulised treatments over the year (approximately 1.4 per day), regardless of whether they were prescribed two or three daily nebulisations. Although the number of patients prescribed two treatments/day was only five, it was the poor adherence in the group prescribed three treatments/day that lay behind this result (adherence rates in those prescribed one and two treatments daily were very similar). It may be that three prescribed treatments per day is one too many for some teenagers trying to manage busy after-school routines. However, it may also be that this group of patients self-select. Having always been poorly adherent, they may be prescribed more treatment to which they continue to remain poorly adherent.
It is interesting to speculate whether there is a limit to the number of nebulised treatments patients and their families can reasonably take. Although this seems intuitive, evidence supporting an upper limit in the literature is difficult to find. Coutts et al. found a trend for adherence to be better in asthmatic children prescribed inhaled medication less frequently [
]. However, the same group went on to study this in more detail in asthmatic children taking two, three or four doses of inhaled steroid per day by a metered dose inhaler and found that patient adherence tended to be similarly poor, whatever the dosing regimen [
We believe that our study population were representative of adolescent patients with CF in the UK. They were a discrete group at the same developmental stage and phase of CF, in the same era of care and from two large regional paediatric CF centres within the same country. They were not a sample of convenience as we recruited all patients in both clinics who fulfilled the eligibility criteria. Their lung function was similar to the 2010 UK CF registry data for 12–15 year olds (median [range] FEV1 81[69–94]%). Despite this, a key limitation to our study was the small sample size. Although collecting and analysing this data was no small undertaking, larger numbers could have allowed us to identify and explore confounders of adherence, such as health (do patients adhere less well when they are sicker?) and family (the effect of multiple children with or without CF) barriers. Another potential limitation concerns the applicability of these results to other CF centres. Not all centres are able to monitor adherence in this way. In those centres where AAD devices are not used, adherence to treatment may be more difficult to sustain without the positive support afforded by electronic data capture.
Although very little is known about actual rates of adherence in CF adolescents, the clinical and psychological changes that occur at this age in this group of patients are well documented. It is the developmental phase where there is the greatest risk for loss of pulmonary function [
]. It is also the time where parents often expect their teenagers to assume greater responsibility for their CF treatment, although, as in many illness groups, these same parents simultaneously view their children's competencies negatively [
Parent–adolescent discrepancies in adolescents' competence and the balance of adolescent autonomy and adolescent and parent well-being in the context of Type 1 diabetes.
]. When teenagers are then perceived to be failing to undertake treatment ‘adequately’ (young people cite reasons for not carrying out prescribed treatments as; not enough time in their days, feeling too well to do treatment and thinking that treatments are not needed [
]), frustrated parents reclaim responsibility for care, fearing their off-springs' health diminishing. This tends to result in conflict and teenagers' further disengagement with treatment. It is perhaps no surprise then that adolescence is the time particularly associated with particularly poor adherence, rates peaking at around 16 years of age [
Adherence to medical treatments in adolescents with cystic fibrosis: the development and evaluation of family-based interventions.
in: Drotar D. Promoting adherence to medical treatment in chronic childhood illness; concepts, methods and interventions. Lawrence Erlbaum Associates,
Mahwah NJ2000: 383-407
], where supporting and motivating teenagers with CF to maintain their treatment regimen becomes a struggle for CF teams.
Our results have several potential clinical implications for healthcare professionals looking after teenagers (both younger and older) with CF. Firstly, as a group of patients known to be at potential risk of poor adherence, the current findings lend weight to CF teams taking an active role in helping families incorporate treatment into their daily schedules, being flexible whenever possible. Secondly, with increased awareness that adherence drops in some patients during holiday periods (particularly in those who are prescribed more than two inhalation treatments per day), comes the opportunity to tailor treatment and treatment-times when possible, to reflect lifestyles, scholastic pressures and recreational pursuits [
]. For example, for those patients with persistent respiratory symptoms, a two-week course of intravenous antibiotic therapy in the run-up to the Christmas holiday period might be a better option than prescribing extra nebulised treatments. Thirdly, for those whose adherence is known to be poor, scheduling clinic reviews immediately prior to major holiday periods may facilitate timely discussion about adherence. Fourthly, in the case of an inhalation regime that is acknowledged to be compromised by all parties, but which is viewed as part of an overall intervention to maintain good adherence in the longer-term, then clinicians might consider permitting planned treatment ‘holidays’ and ‘breaks’ during weekends and/or school holidays. This may have further benefits of reducing patient or parental ‘guilt’ over brief patterns of non-adherence and further enhance collaborative efforts to increase adherence in the longer term. Lastly, given that there are often large gaps and misconceptions in patients' and relatives' CF knowledge, during the phase prior to transition to adult CF services, re-providing information about how the range of inhaled medications work, their rationale for prescription and the long term benefits, could prove useful. Furthermore, it is important to take the opportunity to re-emphasise to patients the importance of incorporating these treatments into daily routines.
In conclusion, we believe data presented herein lend weight to the value of integrating CF care into daily routines, which leads to greater adherence in adolescents. Open discussion with patients and parents and being flexible about treatment breaks may prove useful in achieving optimal adherence in this patient group.
Conflict of interest
None of the authors had any potential, perceived or real conflict of interest in undertaking this study or writing this manuscript.
Acknowledgement
Some of these data were presented in a symposium at the European Cystic Fibrosis Conference in June 2010 in Valencia, Spain.
References
Modi A.C.
Lim C.S.
Yu N.
Geller D.
Wagner M.H.
Quittner A.L.
A multi-method assessment of treatment adherence for children with cystic fibrosis.
Parent–adolescent discrepancies in adolescents' competence and the balance of adolescent autonomy and adolescent and parent well-being in the context of Type 1 diabetes.
Adherence to medical treatments in adolescents with cystic fibrosis: the development and evaluation of family-based interventions.
in: Drotar D. Promoting adherence to medical treatment in chronic childhood illness; concepts, methods and interventions. Lawrence Erlbaum Associates,
Mahwah NJ2000: 383-407
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