Assessment of factors and interventions towards therapeutic adherence among persons with non-cystic fibrosis bronchiectasis

Current approach to bronchiectasis management

Persons with NCFB (pwNCFB) are given a complex regimen of medications, airway clearance techniques and exercise with the primary goals to improve daily symptoms and reduce both number and severity of pulmonary exacerbations [3]. While not fully explored in NCFB, studies completed in the pre-modulator era of cystic fibrosis (CF) identified an average of seven daily therapies and a mean reported time spent on treatment of 108 min [11]. Moreover, those with secondary causes of bronchiectasis have additional management challenges directed at their underlying pathophysiology. Further complicating optimal treatment regimens is the absence of high-quality evidence of their effectiveness [12]. To date, there are no therapeutic options approved by regulatory agencies to attenuate disease progression [13] and treatment regimens are frequently used “off-label”. While increasing development of therapeutics in NCFB is emerging with promising applications, the potential impact(s) on future adherence remain(s) unknown [1].

Airway clearance and mucoactive therapies, considered as standard of care and recommended for all patients, are the backbone of treatment to minimise airway damage, and improve lung function and quality of life [12]. Despite the aforementioned benefits, these treatments are among the most burdensome and time consuming to patients, with associated high expense. Compounding the time requirement towards therapy, proper maintenance of airway clearance devices is critical to attenuate risk of infection [14]. As disease progression occurs, additional airway clearance interventions may need to be included [14].

Benefits of inhaled antibiotics in NCFB include attenuation or cessation of recurrent cycles of infection that normally perpetuate lung damage. In those with frequent exacerbations and/or chronic Pseudomonas aeruginosa infection, recommendations are to commence inhaled antibiotic therapy [15]. Notably, this population was identified as having worse clinical outcomes, including increased frequency and shorter duration to subsequent pulmonary exacerbation, when taking their therapies infrequently [10]. Other pharmacological measures to manage NCFB include inhaled short- and long-acting bronchodilators. While these may be effective in those with documented airway obstruction [16], inhaler adherence is often suboptimal due to coexisting complex therapeutic regimens, limited patient insight on disease and high associated costs [17]. Finally, anti-inflammatory therapy with macrolides has arguably the most robust evidence, with several randomised placebo-controlled trials [18–20] demonstrating lower frequency of pulmonary exacerbation, although downsides include an increased pill burden and exposure to potential adverse effects.

Consequences of suboptimal adherence and associated disease outcomes

Defining and outlining patient expectations are critical to evaluate impact of treatment (table 1), with current evidence suggesting adherence to maintenance therapy for NCFB is poor due to multifactorial reasons (figure 1). McCullough et al. [10] followed a cohort of 75 patients for 1 year using prescription data and strikingly found only 16% were adherent to all treatments. When broken down, about half of the subjects were adherent to their inhaled antibiotics while 41% were adherent to airway clearance techniques. Guan et al. [21] described similar findings, with only 40% of patients reporting continuous use of maintenance therapy. A recent systematic review identified that adherence rates were ∼51% to optimal chest physiotherapy [22].

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FIGURE 1

Factors associated with adherence in non-cystic fibrosis bronchiectasis. Adapted from study by McCullough et al. [52]. Figure partially created with Biorender.com.

Suboptimal adherence to treatment can lead to negative health consequences, including increased pulmonary exacerbations, worse symptom control and lower quality of life. In an observational study performed over a 1-year period, non-adherence was independently associated with increased pulmonary exacerbations compared with patients who were adherent to their inhaled antibiotics [10]. Moreover, non-adherence to chest physiotherapy was associated with lower health-related quality of life. A randomised clinical trial of nebulised colistin administered by a novel delivery device (I-neb adaptive aerosol delivery device; Philips Respironics, Chichester, UK) that records the number of administered doses was unable to demonstrate a benefit compared with placebo; however, this was driven by increased pulmonary exacerbations among non-adherent participants in the intervention group [23]. In a subgroup analysis of those with >80% adherence, the median time to first pulmonary exacerbation was significantly prolonged in the nebulised colistin group compared with the placebo group (168 versus 103 days; p=0.038). Moreover, the adherent cohort experienced fewer pulmonary exacerbations and improved quality of life scores compared with the placebo group. Although robust evidence for airway clearance techniques is modest, they are frequently recommended to help keep the airways clear of mucus. In a systematic review of the impact of chest physiotherapy adherence on health outcomes among those with CF-related bronchiectasis, results were mixed but suggested an association with improved lung function and reduced hospitalisations [22].

Adherence: is more always better?

The current development of novel therapeutics, along with leveraging the potential of those already in existence, has immense potential to fill current gaps in the management of pwNCFB. However, further addition(s) to already complex medical regimens come at the cost of increasing treatment burden to patients. As chronic diseases such as NCFB grow in prevalence, healthcare providers have redirected focus from treatment of acute illness with intense but relatively brief regimens to management of patients living with disease [24]. Moreover, given NCFB rarely occurs in isolation, multimorbid conditions further add to the complexity of therapeutics and compound treatment burden. The degree of burden felt by patients is influenced by a number of factors including older age, illness duration and severity, and multiple comorbidities [25], many of which describe a large proportion of pwNCFB. Moreover, patient perception of burden is dynamic and can change throughout the course of the illness, depending on severity and impact.

While suboptimal adherence is associated with negative consequences as outlined in the previous section, healthcare providers must be cognisant of the precarious balance of adherence and treatment burden. One such approach may entail an approach of “minimally disruptive medicine”, first introduced by May et al. [26] who suggested clinicians may help reduce treatment burden, and consequently attenuate the vicious cycle of suboptimal adherence, by tailoring treatment regimens to the realities of the daily lives of patients by four pillars: 1) establishing the weight of burden through reliable tools, such as patient-reported outcomes, to identify overburdened patients and those with capacity problems; 2) encouraging coordination in clinical practice to manage complexity and comorbidity as the goal, as opposed to specific outcomes; 3) acknowledging comorbidity in clinical evidence through guidelines or clinical trials that include multimorbid patients; and 4) prioritising from the patient perspective as part of shared decision making. While this has been largely unexplored in NCFB currently, delineating the balance of treatment burden with adherence will be a priority for both healthcare providers and patients in the future.

Interventions to increase adherence in bronchiectasis

When evaluating evidence-based interventions to improve adherence in NCFB, prior systematic reviews have failed to identify robust published interventions [27]. However, alternative avenues including patient-centred programmes aimed at improving self-efficacy in bronchiectasis management have been explored. Lavery et al. [28] performed a proof-of-concept randomised trial of an expert patient programme for patients recruited from a specialty bronchiectasis clinic. A small signal of benefit was most evident immediately post-intervention but did not demonstrate any statistically significant differences in self-efficacy or quality of life, attributed in part due to the small study cohort. A bronchiectasis empowerment tool that included an action plan and education sessions for patients was evaluated in a randomised controlled trial of 127 patients in the UK; however, at the primary end-point of 1 year there was no significant difference in self-efficacy scores [29]. Both of these trials reported positive patient-reported feedback, suggesting larger studies of self-management tools are warranted.

Change AdhereNce to treatment in BronchiEctasis (CAN-BE) is a proposed approach to developing and delivering an adherence intervention in bronchiectasis [30]. Based on interviews with patients and healthcare professionals, 12 behaviour change techniques were recommended to be considered in an individualised intervention. These included components such as monitoring, action planning, graded tasks, education regarding the behaviour and outcome, and social support. Multifaceted interventions, in contrast to those solely based on providing disease and treatment education, are expected to have more successful outcomes and should be considered in NCFB.

Lessons learned from other chronic lung diseases

While robust evidence is currently lacking in NCFB, other chronic respiratory diseases, including asthma, COPD and CF, have systematically evaluated interventions to improve adherence. We believe these lessons and ideas provide a framework that may be applied towards pwNCFB and an area of opportunity towards future studies (table 2).

Current gaps and future directions

Suboptimal adherence has clearly been associated with adverse health outcomes in NCFB, including shorter time to [23] and more frequent pulmonary exacerbations [10]. Despite the postulated benefits of adherence, several studies across other chronic lung diseases have failed to consistently demonstrate subsequent improvements in morbidity, mortality, healthcare burden, quality of life and/or patient satisfaction [8]. Discordance of improved adherence and clinical outcomes may be in part due to bias from the Hawthorne effect (i.e. where individuals modify and/or improve behaviour in response to heightened awareness from enrolment in a trial), and may explain observations in several studies of improved adherence in both control and intervention arms [8].

High-quality randomised control trials to evaluate adherence interventions are critical to the optimal management of NCFB, but are lacking due to multifactorial reasons, including absence of dedicated clinical funding, lack of specialist staff for bronchiectasis clinics, perceived low priority of adherence management by clinicians and limited confidence by care providers to challenge patient adherence patterns [30]. Other important factors include heterogeneity of the underlying disease(s) contributing to bronchiectasis and subsequent difficulty in achieving statistical power in subgroup analysis during clinical study design [27]. These hurdles require involvement of multiple centres through dedicated patient registries to increase enrolment as well as standardisation of protocols. Evaluation of adherence to therapy underpins the success of larger research efforts to identify novel and effective treatments. New treatments are emerging, such as brensocatib, a novel anti-inflammatory therapy targeting neutrophilic inflammation that was recently shown to have good efficacy in a phase 2 trial [49]. As such, robust measures of adherence in the era of new developments in therapy will become even more of a priority to all key stakeholders involved (figure 1).