Electronic Monitoring Devices to Support Inhalation Technique in Patients with Asthma: a Narrative Review

Improper inhaling technique is common and is associated with poor patient outcomes. However, digital e-health devices may offer novel opportunities for educational support. This narrative review provides an overview of electronic monitoring devices (EMDs) measuring patient inhalation technique. We summarise their technical features, capabilities and limitations and discuss the steps necessary for implementation in clinical practice. Six EMDs measuring inhalation were identified. The quality of published evidence varied widely. Devices differed in the inhalation technique steps measured, the feedback provided and the type of sensor employed. Sustainability and battery life differed according to whether devices were built into inhalers or add-ons. Nevertheless, all EMDs could reliably capture diverse inhaler technique errors, and some can guide educational interventions and follow-up treatment. In addition, some EMDs may serve as an early warning system for exacerbations. New-generation EMDs can measure patient inhalation technique, yet there is limited data on patient preferences, acceptability of inhaler technique monitoring, cost-effectiveness and the influence of inhaler technique monitoring on clinical outcomes, all representing areas for further research.


Introduction
Inhaled therapy is the mainstay of asthma treatment. Pressurised metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) are the most frequently used inhalation devices. Currently, more than 200 medication-inhaler combinations are available globally [1]. Inhaled therapy is a complex therapeutic modality, with each device requiring a specific inhalation technique for optimal medication delivery. For pMDIs, synchronisation of inhaler actuation and inhalation, slow and deep inhalation and a 5-s breath-hold after inhalation are essential inhalation technique criteria. DPIs are breath-activated, and most devices require a quick and forceful inhaling manoeuvre to deliver medication [1][2][3][4]. The most frequent pMDI errors involve a lack of post-inhalation breath-holding, lack of coordination and speed and depth of inspiration. For DPIs, incorrect preparation, failing to fully exhale before inhaling, and failing to hold your breath after inhaling are common inhalation errors [3,5]. When used correctly, there are no differences in clinical outcomes between available devices [6]. In daily practice, however, inhaler errors occur frequently [5,7]. Notably, poor inhalation technique of asthma patients on both pMDIs and DPIs is significantly associated with poor disease control, increased exacerbations and hospitalisations [2]. Conversely, improving inhaler technique enhances medication delivery, reduces side effects and improves clinical outcomes [2]. Assessing inhalation technique is challenging. Simple methods-such as self-reported questionnaires or physician assessments-are subjective and prone to recall bias [8, 9••, 10••, 11, 12••]. Furthermore, according to a systematic review, as few as 15% of healthcare professionals (HCPs) are able to teach inhalation technique correctly [8]. Electronic monitoring devices (EMDs), also known as digital or smart inhalers, have the potential to objectively monitor and, through feedback, improve patient adherence to therapy. Several new-generation EMDs also provide real-time feedback on the patient's inhalation technique [9••, 10••, 11]. Previous reviews have described EMDs in general [10••, 12••, 13, 14]. This review focuses explicitly on EMDs that are capable of measuring inhaler technique. We summarise their technical properties, clinical effects, patient acceptability, capabilities and limitations and discuss the steps necessary for implementation in clinical practice.

Methods
A semi-structured search informed this narrative review. We searched PubMed, Cross-Ref, Google Scholar and trial registries. We also manually searched the reference lists of the initially identified English language publications of randomised controlled trials (RCTs), (systematic) reviews and guidelines. The search was performed in August and September 2022. We used the key terms 'asthma', 'inhalation technique' and terms related to 'digital inhaler', 'digital sensor' and 'electronic monitoring device' .

New-Generation Electronic Monitoring Devices to Optimise Treatment for Asthma Patients
We identified six devices able to measure inhalation technique: CapMedic ® ; Digihaler ® ; Hailie Sensor ® ; INhaler Compliance Assessment™; Respiro ® ; and Smart AeroChamber ® . Their properties are further specified in the following sections. In addition, images of the EMDs are included in Fig. 1.

CapMedic®
The CapMedic ® device is a sensor currently only attachable to pMDIs. Often pMDIs are used in combination with spacers or valved holding chambers to reduce problems of poor inhalation technique with pMDI alone. Therefore, the GINA guidelines recommend the use of pMDIs with spacers [15,16]. However, for many EMDs, the compatibility with spacers is variable. pMDI EMDs discussed in this review are usually not combined with a spacer or valved holding chamber. This rechargeable device registers medication usage, and the CapMedic ® application also provides an asthma symptom diary facility. The device can give real-time audio-visual feedback on critical errors during inhaler usage by monitoring the number of pMDI shakes before inhalation, the orientation of the inhaler during actuation (angle from the vertical position), patient coordination between device actuation and inhalation, the duration of inhalation and reminder for breath-hold at the end of inhalation. Additionally, the device can measure lung function through spirometry, providing peak inspiratory flow and forced expiratory volume in 1 s. The device sends medication usage and lung function measurements to the CapMedic ® application and a clinician dashboard, and patients can keep an asthma symptom diary on the application. The device is rechargeable, and a full battery lasts for approximately 200 inhalations, or about 100 days of use, assuming two inhalations and lung function assessment tests daily with the same device [10••, 17-20].

Digihaler®
An inbuilt inhalation flow sensor on the Digihaler ® (AirDuo Digihaler ® , ProAir Digihaler ® and ArmonAir Digihaler ® , available in the USA) monitors inhaler use and the following inhalation technique measures: priming the device (e.g. opening the cap), (incorrect) exhalation into the inhaler after priming, and the inspiratory flow rate in litres per minute (L/min). Good inhalation is defined as more than 45 L/min, fair inhalation as 30-45 L/min,

Respiro®
The Respiro ® vibration sensor can be attached to pMDIs, Ellipta ® , Nexthaler ® and Spiromax ® . It can provide digital feedback for several inhalation steps, including inspiratory flow, inhalation duration and inhaler orientation. Data can be uploaded to a paired smartphone (or computer). The mobile application provides personalised guidance for patients. The health provider portal displays a patient data dashboard, notifications regarding poor inhaler technique or adherence, and monthly reports on patient progress, facilitating efficient monitoring of large patient cohorts. The Respiro ® add-ons are nonrechargeable and have a lifetime of 16 to 18 months [10••, 34-37].

Smart AeroChamber®
As stated earlier, clinical guidelines recommend that pMDIs should always be used with spacers. Still, the assessment of inhaler technique and adherence with spacers can be challenging due to the difficulties with objectively assessing correct spacer use and the lack of devices able to provide feedback on spacer use [15,38]. The Smart AeroChamber ® can be combined with most pMDIs [39]. The Smart AeroChamber ® , a rechargeable digital spacer, uses an inhalation flow sensor to detect inhaler technique errors such as multiple actuations, no inhalation, delayed inhalation, excessive inspiratory flow and low inhaled volume. A timestamp is recorded for each controller and reliever actuation. Data is stored on an SD card for transfer to a personal computer [39,40]. The device is rechargeable and must be charged every 4 to 6 weeks. The Smart AeroChamber ® is currently only available for research as a prototype.

Clinical Studies with New-Generation EMDs (Table 2)
The studies we found using new-generation EMDs measuring inhalation technique in asthma patients are summarised in Table 2. There are two small clinical studies examining the CapMedic ® device. An observational study of 23 patients with asthma or chronic obstructive pulmonary disease (COPD) concluded that the CapMedic ® device could detect significant errors in inhaler usage and was more sensitive in identifying and quantifying such errors than observation alone [18]. A small RCT by Paronyan et al. showed improved inhalation technique in 16 patients coached with CapMedic ® data, compared to a control group with patients only shown an inhaler technique video [20]. A larger trial recruiting 50 participants with asthma is currently underway to further examine the impact of the device on inhaler technique and adherence to therapy (NCT04250779). The Digihaler ® has been used in several clinical studies. For example, in a 12-week, open-label trial (n=333), participants with asthma who used the Reliever Digihaler ® System had an 85.3% probability of greater odds of improving their asthma control than those who used standardof-care albuterol inhalers after 3 months (mean odds ratio 1.33; 95% credible interval 0.813-2.050) [22•]. Another study using the ProAir Digihaler ® demonstrated that an increased number of short-acting beta agonist (SABA) inhalations over 5 days predicted an asthma exacerbation [23•]. Additional trials are underway (ClinicalTrials.gov NCT04896645 and NCT04997304) to evaluate whether integrated electronic adherence monitoring of an albuterol rescue inhaler can improve care in children with asthma, and to develop predictive models for asthma exacerbations and response to biologics.
To our knowledge, no published study has examined the relationship between inhalation technique measured using Hailie ® sensors and clinical outcomes in asthma patients [27]. Adherium Limited (ASX: ADR) will perform a two-part clinical study, including both adult (n=50) and adolescent (n=40) asthma patients using AstraZeneca's Symbicort ® pMDI inhaler. The second phase of this study will use inspiratory flow measured by the Symbicort ® pMDI to assess the effectiveness of therapy [29]. No information on this study is available on the ClinicalTrials.gov database yet.   The INCA™ device has been used in several clinical studies, and some included inhalation technique as an outcome measure [31, 32•]. In a multi-centre, randomised, controlled open-label clinical trial, Sulaiman et al. showed a significant improvement in actual inhaler adherence rate at 3 months in patients with asthma using the INCA™ compared to the control group receiving intensive education; however, there was no significant reduction in the rate of technique errors [31]. In a cluster-randomised open-label trial of asthma and COPD patients, O'Dwyer et al. showed significant improvement in actual adherence at 6 months with the use of the INCA™ inhaler due to both person-specific biofeedback on the timing of inhaler use and inhaler technique [32•]. Recently, a 32-week multi-centre single-blind randomised clinical trial (N=220 patients with difficult-to-treat asthma) was conducted in 10 asthma clinics across Ireland and England. In the active group, inhaler use and technique were assessed with the INCA™ device. A control group had adherence and exacerbations assessed by pharmacy records, inhaler technique by visual methods, and asthma control by a validated questionnaire. Both groups had three educational visits over 8 weeks and three treatment adjustment visits over 24 weeks. The adjustments were based on the INCA device's data for the active group and on pharmacy records, visually assessed inhaler technique and asthma control for the control group. Using objective digital data to implement evidence-based asthma management methods resulted in a decrease in high-dose asthma therapies and less escalation to biologic medicines accompanied by significant cost savings [33•].
There are no published clinical studies of the Respiro ® sensor in people with asthma. In a study by Sloots et al. in patients with COPD and concurrent heart failure, adherence to inhaled medication was 98.4%, but 51.9% of inhalations were performed improperly, with 'inhaling too shortly' (1.25 s) being the most common error (79.6%) [35]. A study is underway in children with uncontrolled asthma intending to improve asthma control by providing immediate feedback, including on inhalation technique (Dutch Trial Register NL7705) [36].
A pilot study of 12 participants with COPD evaluated the Smart AeroChamber ® 's usability and investigated its potential impacts on inhaler technique, adherence, long-term systemic medication exposure and clinical outcomes. This study demonstrated the potential value of using a smart spacer to tailor inhaler education for patients with COPD, with potentially similar implications for patients with asthma [39]. A continuation of this study is a multi-centre RCT on the usability and potential clinical effects of using a smart spacer for personalised medication adherence and inhalation technique education in patients with asthma. The control group will receive usual care, and the intervention group will receive personalised education based on the smart spacer data. The primary outcome is the overall feasibility of a definitive trial assessed by patient recruitment speed, participation and drop-out rate. Secondary outcomes are patient and HCP satisfaction, and exploratory clinical outcomes are adherence, inhaler technique, Test of Adherence to Inhalers score, fractional exhaled nitric oxide, lung function, Asthma Control Questionnaire and Work Productivity and Activity Impairment questionnaire [40].

Challenges of New-Generation EMDs
First, in this review, we examined the EMDs capable of measuring inhalation technique factors on top of adherence data. The advanced technology to measure inhalation technique is already very accurate and could provide relevant data: many patients still misuse their devices, consciously or unconsciously. Educating patients about good inhalation technique is essential, and new-generation EMDs can support and tailor this education. However, several challenges exist, including technical issues, patient acceptance, clinical effectiveness evidence, cost-effectiveness and other implementation challenges, as discussed in detail in the next section.

Technical Challenges
One challenge involves the uniformity of inhaler technique definitions. Each of the six EMDs covers different aspects of inhalation technique. All six can measure inspiratory flow, but other parameters vary in availability. Some also assess opening the cap of the inhaler, shaking the inhaler, inhalation duration, inhaler orientation, inhaled volume or whether the patient exhales into the inhaler before inhalation. For example, peak inspiratory flow (PIF) thresholds are used for DPIs (Digihaler ® , INCA™, Respiro ® ) to assess whether minimal PIF is met. For optimum drug delivery with pMDIs, a slower inspiratory flow rate is required compared to DPIs. One digital inhaler that assesses if the inhalation is slow enough is the Respiro ® add-on device for pMDIs.
Another challenge when comparing device output lies in the type of sensor used to measure inhalation technique. The type of sensor used could impact the sensors' accuracy and/or durability. For example, INCA™ uses acoustic sound sensors, Respiro ® uses vibration sensors and the other devices use flow sensors (i.e. the Smart AeroChamber ® , the Digihaler ® and the CapMedic ® ). We only identified one study which looked into the sensitivity of an acoustic sound sensor. They identified that acoustic features were significantly correlated with the user's peak inspiratory flow rate (PIFR). This method in electronic monitoring devices (Diskus ® DPI, Turbuhaler™ DPI and Evohaler™ pMDI) could be employed in future applications to measure inhaler PIFR [41,42]. It might be interesting to know whether one type of sensor is more sensitive or accurate than another. A fundamental difference between the six EMDs identified is whether the sensors are added to or built into inhalers. Add-on inhalers are bulkier for patient use but may be used on multiple successive inhalers and are more efficient and environmentally friendly than single-use built-in sensors.
The way educational feedback is most effectively provided also deserves attention. Most devices can provide direct patient feedback via an interactive application on the patient's phone. In contrast, the INCA™ and Smart AeroChamber ® devices only provide feedback to clinicians when the data is downloaded from the device during a consultation. Direct patient feedback using smartphone applications gives the patient insight into their therapy adherence and supports patient empowerment and self-management. For inhalation technique errors, direct patient feedback is particularly valuable, as it allows the patient to correct their technique in a targeted and continuous manner.
Finally, battery life and, thus, sustainability varies between devices. For example, the Smart AeroChamber ® and the CapMedic ® device consist of a rechargeable battery, whereas the Respiro ® , Digihaler ® , Hailie ® and the INCA™ device include a non-rechargeable battery and must be replaced for continuous use. However, the Digihaler's battery life surpasses the in-pouch shelf life of the inhaler device. Storage capacity also differs. The INCA™ has a 60-dose memory, while the Respiro ® add-on is Bluetooth ® connected to a smartphone application with data storage on the patient's application rather than on the device itself.

Patient Acceptance
Despite the importance of patient acceptability, there is limited research exploring the acceptability of EMDs that monitor inhaler technique [43•]. Patients generally want to feel responsible for their asthma treatment. Many individuals with asthma, including adults and children, are enthusiastic about using smart inhalers, but many issues remain to be resolved [11,44]. Patients may be hesitant to share their adherence and inhalation data captured by an EMD with medical experts. Patients understand the advantages of disclosing this information but also fear some drawbacks [45,46]. The European Lung Foundation chose digital health as the focus of their Patient Organizational Days in 2021-2022, which provided several insights [47]. Patients were eager to utilise applications to track and learn about their health, get prompt advice and cut travel time for appointments. They wanted to establish new relationships with their medical team and keep sickness under control by employing remote monitoring and discussions. On the other hand, they were worried about data security and privacy and wanted to know how others would utilise their data.
Therefore, another crucial challenge is ensuring data privacy and establishing data ownership. The necessity to adhere to General Data Protection Regulation criteria must be considered because many EMDs can provide realtime data to HCPs, and these pathways must be safe and secure. Related ethical concerns of informed consent, trust, privacy, confidentiality and remote patient monitoring require further in-depth considerations [10••, 12••].

Clinical Effectiveness
There remains a need for more evidence on the clinical effectiveness of EMDs. Data suggest that inhaler technique can be improved using EMDs. However, when inhalation technique and adherence improve, do patients experience fewer exacerbations or hospitalisations? What improvements can be gained in quality of life or other patient-reported outcome measures? Are benefits observed in trials similar to real-world settings? In the clinical environment, EMDs measuring inhalation technique need to be compared against nondigital ways of improving adherence and inhalation technique. Longer-term data is also needed-does immediate smart feedback on inhaler technique translate into better technique in the longer term (i.e. after 1 or 2 years)?

Cost-Effectiveness
Some data on the cost-effectiveness of interventions to improve adherence and inhalation technique for inhaled medication generally indicates a good value for money [48][49][50]. Lewis et al. studied the direct and indirect costs of nonadherence due to inhalation technique errors by asthma and COPD patients [51]. They showed that the direct annual expenses per patient with asthma or COPD in Spain, Sweden and the United Kingdom were €1,421, €1,183 and €963, respectively. Part of these expenses (€109, €55 and €21) was expected to be partially attributable to inhaling mistakes. Indirect expenditures doubled these estimated costs: €271, €466 and €506, respectively [51].
However, the cost-effectiveness of EMDs in asthma is yet to be determined -for example, whether EMDs are only cost-effective for specific subgroups of asthma patients, such as those at high risk of poor adherence or those with uncontrolled asthma. Cost-effectiveness could be demonstrated if improved inhaled drug delivery avoids exacerbations, work productivity losses or prevents patients from switching to more expensive or harmful medicines, such as oral corticosteroids (OCS) or biologic therapy. Patients receiving OCS or biologics may be another interesting population to study. Some patients have low inhaled corticosteroids (ICS) adherence when ICS maintenance therapy is necessary to maintain asthma control [52]. There is potential to increase adherence in these individuals and enhance clinical outcomes. Another important patient group may be patients with asthma or COPD who initiate inhaler medication. Targeting these patients early in their illness may prevent poor inhaler and adherence habits from becoming ingrained in their daily routines. One study found that a 3-month initial period of electronic adherence monitoring is sufficient to provide insights into whether the individual will have good adherence and asthma control in the longer term [53•].

Implementation Challenges
For EMDs to be implemented into routine healthcare, they must also be easy to use by HCPs. In addition, the time and personnel needed to monitor patients remotely and react to any EMD notifications are essential to consider. One problem is the current proliferation of software and apps required for each device. Ideally, the data generated by smart inhalers should be simple to understand, compatible with other smart inhalers, and easily uploaded to a single platform for patient management.
Lastly, successful implementation requires consideration of costs and reimbursement issues. The costs of EMDs differ between $100 to $500 unit price (in US dollars) [54]. More studies are needed to evaluate whether the additional EMD purchasing costs and the direct and indirect healthcare costs due to non-adherence and poor inhalation technique outweigh each other. Reimbursement is another challenge [55]. Will smart inhalers be sold over the counter or covered by insurance? Manufacturers may also incorporate the smart inhaler into the inhalation device (built-ins) to include it in the regularly covered asthma medications.

Opportunities for New-Generation EMDs in Asthma Therapy
Some of the EMDs discussed offer feedback on aspects of inhaler technique that are frequently challenging to evaluate clinically, such as whether or not there was sufficient coordination between actuation and inhalation or adequate inspiratory flow. These factors are difficult or impossible for patients to evaluate on their own or with the assistance of HCPs. EMDs offer the possibility to objectively identify most of the critical steps of good inhalation technique and also long-term at home in the patient's daily life. Also, clinicians frequently overestimate adherence and inhalation technique [8]. The use of digital adherence monitoring will probably show that many more patients than previously thought are not using their prescribed inhalers effectively [56].
Secondly, it is possible to identify both intentional and unintentional non-adherence over time due to the composite assessment of adherence produced by the combination of temporal and inhaler technique information [57]. For example, regular use of an inhaler but with poor technique is likely to suggest unintentional non-adherence as the individual is routinely using their medication but not using it correctly. This knowledge can help HCPs distinguish between difficult-to-control asthma and severe asthma, allowing for patient-centred interventions and possibly preventing unnecessary progression to OCS or biological therapies. The use of EMDs in patients with asthma to track and manage medication adherence, including inhalation technique as an essential factor, shows promise for enhancing clinical outcomes and lowering the financial burden.
Thirdly, according to a posthoc analysis of the Formoterol and Corticosteroids Establishing Therapy (FACET) study, the days preceding an acute exacerbation are marked by a decline in lung function and an increase in the use of rescue inhalers [58]. Only the second hypothesisthat a higher rescue use was a significant predictor of a severe future exacerbation-was verified in the FACET study. However, preliminary findings from another study investigating the real-life use of the ProAir Digihaler ® by asthma patients revealed that increased rescue use and changes in inhalation technique (PIF and inhalation volume) were predictors of an exacerbation. In a trial with 360 patients with asthma using the Digihaler ® , 64 of whom had an exacerbation, PIF decreased around 5 days before the exacerbation and then rose to baseline over a similar period [42]. These data suggest that EMD monitoring of PIF may serve as an early warning system for exacerbations and provide an opportunity for intervention.

Future Perspective of New-Generation EMDs
The number of EMDs for patients with airway disease has increased exponentially in recent years, potentially raising the standard of care that an HCP can provide for asthma patients. Simple counting tools have been replaced by highly advanced inhaler attachments or built-ins that offer patients individualised feedback, guided inhaler use, inspiratory flow measurements and audio-visual reminders while providing HCPs with detailed insights into patient behaviour and inhalation technique during daily life at home.
Further development of EMDs should focus on overcoming the current technical limitations described above, with longer battery life, a simple transition from an empty inhaler to the next one, and an accessible phone application with personalised, direct and detailed feedback. Patient preferences should be taken into account when designing EMDs. An international Discrete Choice Experiment is ongoing to determine which attributes and characteristics of currently available EMDs for asthma inhalers are most valued by asthma patients and by asthma HCP [45].
Additional research is needed in three main areas: patient acceptance, clinical outcome measures (i.e. real-world data and longer follow-up-up trials) and cost-effectiveness.

Conclusions
In conclusion, a handful of EMDs can now measure the essential aspects of inhalation technique. Further studies should focus on patient preferences and acceptance, the impact on clinical outcomes, and the cost-effectiveness of these devices.

Open Accress
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