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\begin{document}

\title{Interventions to improve adherence in children with asthma: A systematic
review}



\author[1]{Christina Pearce}%
\author[1]{Amy Chan}%
\author[2]{Tracy Jackson}%
\author[3]{Louise Fleming}%
\author[4]{Holly Foot}%
\author[5]{Andrew Bush}%
\author[1]{Robert Horne}%
\affil[1]{University College London}%
\affil[2]{The University of Edinburgh}%
\affil[3]{Royal Brompton and Harefield NHS Foundation Trust}%
\affil[4]{The University of Auckland}%
\affil[5]{Imperial College London}%


\vspace{-1em}



  
  \date{May 29, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Introduction: Non-adherence to inhaled corticosteroids (ICS) in children
with asthma leads to significant morbidity and mortality. Few
interventions to improve adherence have been effective and little is
known about what contributes to intervention effectiveness. This
systematic review summarises the efficacy of these interventions and the
characteristics of effective interventions to inform future studies
aiming to improve adherence to ICS in children with asthma. Methods:
PubMed, Embase, PsychINFO, Medline, Web of Science, and International
Pharmaceutical Abstracts were systematically searched on the 3rd of
October 2020 for randomised control trials measuring adherence to ICS in
children with asthma. A narrative synthesis was conducted focusing on
intervention efficacy and study reliability. Intervention content was
coded based on the NICE guidelines for medicines adherence (The
Perceptions and Practicalities Approach, PAPA) and Behaviour Change
Techniques (BCT), to determine the effective aspects of the
intervention. Results: Of 240 studies identified, 25 were eligible for
inclusion. Thirteen of the twenty-five studies were categorised as being
highly reliable. Nine of the thirteen studies were effective at
increasing adherence and six of those met the criteria for a PAPA
intervention. Conclusion: Adherence interventions in children with
asthma have mixed effectiveness. Effective studies tended to be of
higher quality, were tailored to individuals perceptual and practical
adherence barriers, and used multiple BCTs. However, due to the small
number of included studies and varying study design quality, conclusions
drawn here are preliminary. Future research is needed to test a
PAPA-based intervention with a rigorous study design as outlined in this
review%
\end{abstract}%



\sloppy


\section*{Interventions to improve adherence in children with
asthma:}

{\label{interventions-to-improve-adherence-in-children-with-asthma}}

\section*{A systematic review}

{\label{a-systematic-review}}

Christina Joanne Pearce\textsuperscript{1, 2}, Amy Hai Yan
Chan\textsuperscript{1, 2,5}, Tracy Jackson\textsuperscript{2}, Louise
Fleming\textsuperscript{2, 3, 4}, Holly Foot\textsuperscript{5}, Andy
Bush\textsuperscript{2, 3, 4} and Rob Horne\textsuperscript{1, 2,}

Affiliations: \textsuperscript{1} School of Pharmacy, Department of
Practice and Policy, University College London, London, Greater London,
United Kingdom, \textsuperscript{2} Asthma UK Centre for Applied
Research, \textsuperscript{3}Paediatric Respiratory Medicine, Royal
Brompton Hospital, London, Greater London, United Kingdom, SW3
6NP,\textsuperscript{4}National Heart and Lung Institute, Imperial
College London, London, Greater London, United Kingdom, SW7
2AZ,\textsuperscript{5} School of Pharmacy, The University of Auckland,
Auckland, New Zealand.

\textbf{Corresponding author:} Christina Joanne Pearce, UCL School of
Pharmacy, Research department of Practice and Policy, BMA/Tavistock
House, Mezzanine Floor, BMA House, Tavistock Square, London WC1H 9JP,
United Kingdom. Email: christina.pearce.15@ucl.ac.uk

\textbf{Take home message:} Interventions to increase adherence to ICS
can be effective in children with asthma, but more rigorous intervention
methods are needed. Patients' beliefs about ICS and their ability to
adhere should be targeted in future patient-tailored interventions.

\textbf{Key words:} Adherence; diagnosis; asthma; intervention; inhaled
corticosteroids; systematic review

\subsection*{Abstract}

{\label{abstract}}

Introduction: Non-adherence to inhaled corticosteroids (ICS) in children
with asthma leads to significant morbidity and mortality. Few
interventions to improve adherence have been effective and little is
known about what contributes to intervention effectiveness. This
systematic review summarises the efficacy of these interventions and the
characteristics of effective interventions to inform future studies
aiming to improve adherence to ICS in children with asthma.

Methods: PubMed, Embase, PsychINFO, Medline, Web of Science, and
International Pharmaceutical Abstracts were systematically searched on
the 3\textsuperscript{rd} of October 2020 for randomised control trials
measuring adherence to ICS in children with asthma. A narrative
synthesis was conducted focusing on intervention efficacy and study
reliability. Intervention content was coded based on the NICE guidelines
for medicines adherence (The Perceptions and Practicalities Approach,
PAPA) and Behaviour Change Techniques (BCT), to determine the effective
aspects of the intervention.

Results: Of 240 studies identified, 25 were eligible for inclusion.
Thirteen of the twenty-five studies were categorised as being highly
reliable. Nine of the thirteen studies were effective at increasing
adherence and six of those met the criteria for a PAPA intervention.

Conclusion: Adherence interventions in children with asthma have mixed
effectiveness. Effective studies tended to be of higher quality, were
tailored to individuals perceptual and practical adherence barriers, and
used multiple BCTs. However, due to the small number of included studies
and varying study design quality, conclusions drawn here are
preliminary. Future research is needed to test a PAPA-based intervention
with a rigorous study design as outlined in this review.

\par\null

\section*{Introduction}

{\label{introduction}}

Asthma is the most common chronic non-communicable disease in children
worldwide \textsuperscript{1}. Asthma prevalence is higher in children
in Europe (8.9\%), compared to the rest of the world
(7.2\%)\textsuperscript{2} but varies between countries
\textsuperscript{3}. Most children with asthma achieve good disease
control with maintenance low dose inhaled corticosteroids (ICS), which
are effective at preventing most asthma hospitalisations and deaths
\textsuperscript{4}. However, some children remain poorly controlled
despite being prescribed high-dose ICS treatment, often due to poor
adherence. This contributes to suboptimal asthma control and severe
attacks\textsuperscript{5; 6}. Up to half of patients attending tertiary
care paediatric asthma clinics are non-adherent (defined as taking less
than 80\% of their prescribed dose)\textsuperscript{7}.

The Global Initiate for Asthma (GINA) highlights that suboptimal use of
asthma treatment is a patient-specific barrier that contributes to the
burden of asthma \textsuperscript{8}. Similarly, the UK National Review
of Asthma Deaths reported that 67\% of asthma deaths were avoidable, and
one of the most important avoidable factors was low ICS adherence in the
month and/or year before death \textsuperscript{9}.

Many interventions have been developed to address the issue of poor ICS
adherence in children. A meta-analysis in adults and children identified
that interventions for improving adherence in asthma can be
effective\textsuperscript{10}. However, the meta-analysis did not
examine the intervention characteristics e.g. content, channel of
delivery and context of the intervention, which form the three
components of behaviour change framework (3CBC\textsuperscript{11}) in
relation to intervention efficacy. It is important to be able to
identify characteristics of effective interventions so that they may be
applied in practice.

Moreover, the reliability of the diagnosis of asthma and the adherence
measurement tool have not previously been used to identify high
reliability interventions. If patients are diagnosed with asthma
incorrectly, non-adherence to a treatment that is therefore unnecessary
is logical. Similarly, if adherence is overestimated in studies using
unreliable adherence measurements, then the conclusions drawn from the
studies will also be inaccurate. By investigating these factors, the
data presented in this review are likely to be more relevant to practice
as they represent a rigorous test of the intervention.

The National Institute for Clinical Excellence (NICE) has developed
guidelines intended to aid the design of adherence support for long term
conditions at any stage of the life span \textsuperscript{12}. The
guidelines apply the Perceptions and Practicalities Approach
(PAPA\textsuperscript{13} E-image 1). This approach recognises that
adherence varies within the individual, over time and across treatments.
Adherence/non-adherence is best understood in terms of the interaction
between an individual and a particular treatment. It is a variable
behaviour rather than a trait characteristic. The Perceptions and
Practicalities Approach (PAPA) conceptualises adherence as including
both intentional and unintentional non-adherence.

The application of the PAPA approach to adherence interventions has the
following key features firstly, the need for a no-blame approach as
patients are often reluctant to admit to non-adherence, or to concerns
about the treatment, as they fear that this may be interpreted by the
clinician as doubting their expertise. Hence, non-adherence and the
reasons for it are often hidden. The second key feature is the need to
tailor support to address both \emph{perceptions} (e.g. beliefs about
asthma and its treatment) and \emph{practicalities} (e.g. clear
instructions on inhaler technique, establishing a medication routine).
Both perceptions and practicalities influence the patient's motivation
and ability to start and continue taking the treatment. Indeed, research
in asthma has shown beliefs about ICS are often important perceptual
barriers to adherence, particularly doubts about the personal need for
regular inhaler use particularly in the absence of symptoms and concerns
about corticosteroids \textsuperscript{14; 15}.

This systematic review aims to address these research gaps by 1.
Specifically examining adherence in children with asthma 2. Using
quality indicators to identify those studies that may be more
informative, and3. Examining the characteristics of adherence
interventions to identify features that may be relevant to practice.

\section*{Methods}

{\label{methods}}

\subsection*{Search Strategy}

{\label{search-strategy}}

PubMed, Embase, PsychINFO, Medline, Web of Science, and International
Pharmaceutical Abstracts databases were searched systematically from the
date of database inception until 3\textsuperscript{rd} October 2020 to
identify relevant literature. MeSH, Emtree and truncated terms were used
where applicable (E-table 1). Key search terms were: asthma, child,
Intervention, adherence and randomized. All authors were contacted via
email or, if not reachable via this route, by ResearchGate messaging for
further details about the studies.

\subsubsection*{Study selection}

{\label{study-selection}}

Authors CP and TJ reviewed the abstracts, followed by the full texts
against the inclusion/exclusion criteria. Where there were differing
opinions a third, opinion was sought (RH). Inclusion criteria were based
on the Participant-Intervention-Comparison-Outcome-Study Design (PICOS)
framework. Any interventions that focused on adherence to ICS with at
least one outcome measure of adherence and used a randomised control
trial (RCT) design were included. The comparison group was either usual
treatment or basic education arms. Articles were included where the full
text was written in English, and where the population of interest was
patients aged 0-18 years old with a diagnosis of asthma. Although many
preschool children with wheeze do not respond to
ICS\textsuperscript{16}, studies often recruit younger children and
therefore this age-range was intended to avoid missing relevant
articles. If they do not have the treatable trait of airway eosinophilia
likely to respond to ICS \textsuperscript{17} this will be highlighted
in the section regarding reliability of the criteria for asthma
diagnosis. Studies were excluded if they did not meet the above criteria
or if they were an RCT comparing two medications only, or where the
majority of participants were not children (e.g. the mean age of
participants was over 18 years or only adults were recruited).

\subsubsection*{Data Extraction and
Synthesis}

{\label{data-extraction-and-synthesis}}

Following full-text review, CP and TJ extracted details of: study
characteristics (setting, number of participants, diagnosis criteria,
intervention and control descriptions and the outcome of interest);
Effectiveness; Risk of Bias (RoB); and Behaviour change techniques
(BCTs); target of the BCTs; relationship to PAPA.

Intervention Content

{\label{intervention-content}}

Intervention content were coded for PAPA as follows: Level 1
(intervention only targeted perceptions or only practicalities and not
tailored); Level 2 (both perceptions and practicalities targeted but not
tailored or only targeting one component (perceptions or practicalities)
and tailored) and Level 3 (both perceptions and practicalities targeted
and tailored to the individual).

Specific components within the intervention for changing adherence
(Behaviour Change Techniques; BCTs) were also coded independently using
BCT taxonomy V1 app \textsuperscript{18}. Any differences in the
selected BCTs were discussed until consensus was reached (Table 1).

Risk of Bias

{\label{risk-of-bias}}

RoB was assessed independently using the Cochrane Risk of Bias
Handbook\textsuperscript{19} by CP, AC and HF using the Covidence
platform (\emph{www.covidence.org}) to record coding decisions and
consensus discussions. The RoB score was based on the adherence outcome.
Each study was scored across five domains: selection bias; performance
and detection bias, attrition bias and reporting bias, and was scored as
either low, high or unclear risk for each study. Authors were contacted
for clarity when information relating to domains seemed unclear.

Study Reliability

{\label{study-reliability}}

To ascertain which interventions were truly effective, study reliability
was considered. Although other validated tools have been used to assess
quality such as the Grading of Recommendations, Assessment, Development
and Evaluations (GRADE) tool \textsuperscript{20} the authors felt that
there were several crossovers between risk of bias, the reliability
scores, the 3CBC approach and in particular, the indirectness section of
the GRADE tool and based on the aim of this review the reliability
measurements would be more useful when considered with RoB. Both
diagnosis and adherence measures can range from being subjective to
objective, therefore considering the reliability of the approaches used
is key for determining study reliability. Through multidisciplinary team
discussions (including with respiratory physicians, pharmacists and a
health psychologist) a coding hierarchy that considered the reliability
of the asthma diagnosis and adherence measurement used was created and
applied to the specific studies within this review (E-table 2).

Based on the RoB, the reliability of the asthma diagnosis, and the
objectivity of the adherence measurement, the most reliable and least
biased studies were used to ascertain what components constituted an
effective intervention. Previous literature suggests that optimising the
context, channel of delivery, and content of the intervention is
important for intervention effectiveness \textsuperscript{11}, and thus
the 3CBC \textsuperscript{11} was also applied to this review.

Studies were summarised by a narrative synthesis. Meta-analysis was not
conducted due to the wide study heterogeneity in terms of setting,
asthma diagnosis criteria, and outcome measures used. The study protocol
is published on PROSPERO
(\emph{https://www.crd.york.ac.uk/prospero/\#searchadvanced}) (ref:
CRD42016029213).

\section*{Results}

{\label{results}}

\subsection*{Search Results}

{\label{search-results}}

The literature search retrieved 255 articles. An additional nine were
identified from other sources. Twenty-two duplicate articles were
removed before abstract screening. Based on abstract screening, 202
papers were excluded and a further 13 papers were excluded based on the
full text. Main reasons for exclusion were: study design not an RCT; no
usual care control group; medication adherence not included as a usable
outcome; trial compared medications or was conducted in adults.
Twenty-five studies were included in the narrative
synthesis\textsuperscript{21-45}; see full PRISMA diagram (Figure 1).

Figure 1: PRISMA flow diagram showing study selection

\subsection*{Narrative Synthesis}

{\label{narrative-synthesis}}

\subsubsection*{Study characteristics}

{\label{study-characteristics}}

Effect on adherence

{\label{effect-on-adherence}}

Less than half of the interventions (44\%, 11/25) showed significant
improvement in adherence in the intervention groups compared to the
control groups \textsuperscript{23-25; 32-34; 36-38; 41; 44} (Table 2).

\subsubsection*{Study Reliability}

{\label{study-reliability-1}}

Although half of the studies were reported as effective at increasing
adherence the study reliability varied widely (Table 3). A wide range of
criteria were used for the diagnosis of asthma and therefore the patient
sample included in each study was heterogeneous. Where reported, most
diagnoses were based on guidelines such as GINA, National Heart, Lung,
and Blood Institute (NHLBI) \textsuperscript{24; 25; 35} or a physician
diagnosis plus a prescription for ICS \textsuperscript{23; 26; 28-30;
37} (50\%, 9/18). Just under half (44\%, 8/18) reported using an asthma
diagnosis given by the emergency department
physician\textsuperscript{21; 32; 38} , where patients asthma symptoms
will have been directly observed by physicians, or by diagnosis from
medical records \textsuperscript{22; 27; 31; 34; 36}. Asthma diagnosis
criteria was generally poorly reported.

Based on the coding hierarchy which considers the reliability of the
asthma diagnosis (E-table 2), seven studies used reliable means to
diagnose asthma in their participants \textsuperscript{21; 23; 24; 32;
36-38}. Three studies used less reliable methods \textsuperscript{25;
34; 35} and a further seven used unreliable diagnostic
methods\textsuperscript{22; 26-31}. In one study the method of diagnosis
of asthma was unclear \textsuperscript{33}.

Adherence measurement varied with studies using objective and subjective
measures. Based on our coding hierarchy of objectivity of adherence
measurements (E-table 2), most studies used more objective
measurements\textsuperscript{23; 24; 28; 31; 33; 34; 36; 37} or both
objective and subjective measures \textsuperscript{26; 27; 35}. Six used
subjective measurements of adherence only \textsuperscript{21; 22; 25;
30; 32; 38}and for one study, the method of adherence measurement was
unclear\textsuperscript{29}. Based on the RoB, reliability of asthma
diagnosis and objectivity of the adherence measurement within each study
the reliability of the evidence can be summarised (Table 3).

\subsubsection*{Risk of Bias}

{\label{risk-of-bias-1}}

Risk of bias within studies

{\label{risk-of-bias-within-studies}}

Nearly one third of the studies were considered low
risk\textsuperscript{21; 23; 24; 34; 38; 39; 41; 43} , with most (n=10)
being considered moderate risk \textsuperscript{22; 26; 30; 32; 33;
35-37; 40; 44}. Six studies were considered high
risk\textsuperscript{25; 27-29; 31; 42} (Table 3 and Figure 2).

Figure 2: Risk of Bias within and across studies

Risk of bias across studies

{\label{risk-of-bias-across-studies}}

The main bias identified was performance bias. Overall, RoB was low for
most studies in terms of selection bias (random sequence generation);
detection bias (blinding of outcome assessment) and reporting bias
(selective reporting bias). Section bias (allocation concealment) was
often low or unclear and was generally poorly reported. Attrition bias
(incomplete outcome data) was frequently unclear or high risk (Figure
2).

\subsubsection*{Reliability of the
evidence}

{\label{reliability-of-the-evidence}}

The most reliable studies (i.e. moderate or high reliability based on
asthma diagnosis and adherence measurement criteria) and low/ moderate
RoB are discussed in more detail below. Nine of the thirteen studies in
this category were effective at increasing adherence\textsuperscript{23;
24; 32-34; 36-38; 41} and four were ineffective\textsuperscript{21; 26;
35; 39}. The following section compares the nine effective studies with
the four ineffective studies within this high reliability group. Of
those studies which reported effectiveness for increasing adherence,
only one study was not considered to be in the high reliability group.

Components of effective interventions

{\label{components-of-effective-interventions}}

This section will summarise the findings of this systematic review based
on the 3CBC framework \textsuperscript{11} in order to critically
appraise the effectiveness of the components within the most reliable
intervention study evidence.

\subsubsection*{Context}

{\label{context}}

The eight effective studies were conducted in
Brazil\textsuperscript{24}; Greece \textsuperscript{41};New
Zealand\textsuperscript{23; 32}; China\textsuperscript{44}; the
USA\textsuperscript{38}; the UK \textsuperscript{34; 36}; and the
Netherlands \textsuperscript{37}. The ineffective studies were conducted
in the USA \textsuperscript{21; 26; 28; 31; 39; 42},
Taiwan\textsuperscript{35}, Brazil\textsuperscript{45}, the
Netherlands\textsuperscript{40} and Sweden\textsuperscript{43; 46}.
Effective studies took place in an emergency care setting
\textsuperscript{23; 38}; primary care \textsuperscript{24; 34};
hospital outpatients\textsuperscript{33; 36; 37; 41; 44}; and in the
community\textsuperscript{32; 44}. The ineffective studies took place
in: emergency care \textsuperscript{21; 39}, in the
community\textsuperscript{26; 40}, primary care\textsuperscript{42; 43}
and in hospital outpatients \textsuperscript{35; 43; 45}.

There are no data regarding whether or not the interventions used a
no-blame approach \textsuperscript{11} but three of the high reliability
effective studies were clearly tailored to the
patient\textsuperscript{24; 32; 33; 41} compared with only one of the
ineffective studies \textsuperscript{35}.

\subsubsection*{Channel of Delivery}

{\label{channel-of-delivery}}

Seven of the high reliability effective studies used technology to
deliver the intervention including using electronic monitoring devices
(EMDs \textsuperscript{23; 33; 36; 37; 41}), the
telephone\textsuperscript{24}, a patient and health-care provider
app\textsuperscript{44} and a SMS-based system \textsuperscript{37}.
Seven of the ineffective studies used technology to deliver the
intervention via an educational video\textsuperscript{42}, website and
monthly telephone calls \textsuperscript{26}, SMS text reminder and tips
(not personalised) \textsuperscript{39}, a smartphone
app\textsuperscript{40; 43} and via the internet
alone\textsuperscript{35}. Different health care practitioners were
involved in the interventions. Effective studies involved
Pharmacists\textsuperscript{23; 37}, nurses \textsuperscript{23; 24; 32;
33; 36; 41; 44}, specialist physicians \textsuperscript{32; 33; 36-38;
44}, community health workers \textsuperscript{32} and
researchers\textsuperscript{37}. In one study (1/8), the only channel
was a letter sent from the patients' GP \textsuperscript{34} to the
parents of the child with asthma. The ineffective studies used limited
contact with any health care practitioner \textsuperscript{21},
pharmacist\textsuperscript{40},nurse \textsuperscript{26; 35; 42; 45}
and physician \textsuperscript{35; 42; 43}.

\subsubsection*{Content}

{\label{content}}

Summary of perceptions and practicalities targeted by adherence
interventions

Of the nine effective and highly reliable studies, six met the criteria
for Level 3 (67\%; \textsuperscript{24; 32; 33; 36; 38; 41} (Table 4).
The three other effective and high reliability studies were categorised
as Level 1 or Level 2 with one untailored intervention focusing
practical and perceptual factors\textsuperscript{34}, one focusing only
on practical factors \textsuperscript{23} and one targeting
practicalities in a tailored way \textsuperscript{37}. Of the highly
reliable studies only four were not effective- two were categorised as
Level 3 \textsuperscript{26; 35}, one was categorised as Level
2\textsuperscript{39} and one was categorised as Level
1\textsuperscript{21}.

Only two effective studies were classified as low reliability and
categorised as Level 3 \textsuperscript{25; 44}. The ineffective and low
reliability studies were either classed as Level 1 (no
tailoring)\textsuperscript{27; 42; 43}, Level 2 perceptual
only\textsuperscript{29; 30}, or both but not tailored
\textsuperscript{22}or Level 3 \textsuperscript{28; 31; 40; 45}.
Therefore, only six studies using Level 3 PAPA were not effective (6/25,
24\%), four of which were classed as low reliability studies. Overall,
only 18\% (2/11) of high reliability studies using Level 3 of the PAPA
did not result in effective studies.

Summary of Behaviour Change Techniques used

The most commonly used Behaviour Change techniques within effective and
highly reliable study interventions were: Non-specific
rewards\textsuperscript{33}; Prompts/cues \textsuperscript{23; 24; 33;
34; 36; 37; 39; 41; 44}; Feedback and Monitoring \textsuperscript{23;
33; 36-38}; Pharmacological support (this often involved providing free
medications in countries where medications were not free and providing a
longer-term supply when the medications were free) \textsuperscript{23;
24; 33; 34; 38}; Instruction on how to perform a
behaviour\textsuperscript{32; 33; 36; 38; 41} and Information about
antecedents\textsuperscript{32; 41}. Relevant to the age of the
participants, the BCTs most often targeted both parent and child with
the aim (primary or secondary outcome) of improving the child's
adherence to ICS. Only in one instance did the BCT pharmacological
support target only the parent in the form of a letter to encourage the
parent to pick-up the child's ICS prescription \textsuperscript{34}.
Four further studies specified that the interventions targeted the child
specifically\textsuperscript{23} and these were often with older
children\textsuperscript{24; 28; 29}. For extracted examples of common
behaviour change technique and the studies they were used in see Table
5. For full details of the behaviour change technique extraction for
each included study see Table 1.

\section*{Discussion}

{\label{discussion}}

\subsection*{Summary of the Evidence}

{\label{summary-of-the-evidence}}

This is the first review to summarise effective interventions to
increase adherence in children with asthma, taking into account the
reliability of the studies and the behaviour change framework and
techniques used in a clinically meaningful way. Previous reviews of
adherence interventions in adults and children have shown that only half
of interventions are effective at increasing
adherence\textsuperscript{10}. Similarly, we found that only nearly half
of the included studies (11/25) were effective at significantly
increasing adherence \textsuperscript{23-25; 32-34; 36-38; 41; 44}. We
then explored the crucial factors for an effective intervention to
increase adherence.

Of the thirteen studies that were effective, nine were considered highly
reliably \textsuperscript{23; 24; 32-34; 36-38; 41}. By comparing the
effective and reliable studies (9/25) (accurate asthma diagnosis,
objective adherence measure and low/moderate RoB) to the unreliable or
ineffective studies this review should inform the development of future
interventions. In terms of context high reliability interventions
carried out in the UK (2/25) and New Zealand (2/25) were most likely to
be effective. High reliability Interventions carried out in the USA were
most often ineffective (6/25 versus 1/25 that was effective). However,
regarding healthcare context there were no differences between different
healthcare settings such as primary or secondary care. Three of the four
high reliability but ineffective studies were not tailored to the
patient group \textsuperscript{21; 39; 47}. This highlights the
importance of tailoring as it has been well reported that tailoring is
associated with more effective interventions \textsuperscript{12}.

The findings of this review support the use of technology as a channel
to deliver the adherence intervention including electronic monitoring
devices for measuring adherence and patient and health-care provider
apps and telephone calls. Healthcare practitioner type is not as
important as face-to-face contact while providing digital interventions.
This finding supports a previous recent review based on digital
interventions in long-term conditions \textsuperscript{48}. Those
planning an adherence intervention should therefore consider the amount
of contact alongside digital interventions as a key component to future
effectiveness.

In terms of content, six out of the nine reliable effective
interventions were coded as Level 3 PAPA \textsuperscript{24; 32; 33;
36; 38; 41}. Three high reliability and effective studies did not meet
the criteria for Level 3 PAPA \textsuperscript{23; 34; 37}. Overall,
only two of the highly reliable studies based on Level 3 PAPA did not
result in effective interventions \textsuperscript{26; 35}. The two
studies had moderate risk of bias and did not involved face-to-face
contact with a healthcare professional.

PAPA is easy to apply when developing an intervention as it simply
highlights the effective minimal ingredients for change in
adherence\textsuperscript{49}. This review found that currently
developed interventions in this area largely neglect the role played by
patient beliefs about asthma and ICS. Research shows that these are
often important determinants of non-adherence in
adults\textsuperscript{50; 51} and there is immerging evidence of
relevance in children \textsuperscript{52}: in terms of parental
\textsuperscript{53; 54} and adolescent beliefs \textsuperscript{14;
15}. Patient's perceptions that are of particular importance are beliefs
about their personal need for treatment (even in the absence of
symptoms) and concerns about steroid safety. These issues are important
because necessity and concern beliefs may be the drivers of adherence as
they influence motivation to adhere to treatment \textsuperscript{55;
56}.

The most common BCTs used in effective interventions were prompts/cues
(e.g. reminders), feedback and monitoring; pharmacological support and
instruction of how to perform a behaviour. Each BCT was found to be most
effective as part of complex interventions when tailored to the patient.
It is currently unknown how many and what combination of BCTs are likely
to increase the effectiveness of an intervention. However, this review
is the first to show that particular BCTs are important to consider when
developing a tailored intervention for increasing adherence in children
with asthma.

\subsubsection*{Strengths and
Limitations}

{\label{strengths-and-limitations}}

Due to the heterogeneity of the adherence outcomes, limited availability
of raw data and a small number of eligible studies a meta-analysis was
not possible within this review.

This systematic review focuses on adherence as an outcome as opposed to
clinical health outcomes as unlike within the adult literature, few
studies in paediatric asthma include both adherence and clinical
outcomes. Focusing on adherence therefore allowed a greater number of
studies to be synthesised. Ideally intervention studies should have an
objective reliable clinical outcome as well as an adherence outcome to
account for potential patient manipulation of the adherence measurement
and for those patients that may have low adherence despite good control
(likely over-medicated). However, unlike in some other conditions,
adherence to ICS has been shown to be highly correlated with objective
clinical outcomes \textsuperscript{57} and therefore the use of
adherence as a primary focus for this review is a reasonable proxy.

Most of the interventions had a moderate RoB which was increased by the
high level of performance bias which is common in behavioural
interventions. This is due to the lack of ability to blind patients and
personnel to the purpose of the study, however, many of the studies
tried to counteract that using deception (where ethically permitted).
This included objective electronic monitoring devices also for control
groups and additional measurements to distract from the adherence data
collection. The studies often had low selection bias (for random
sequence generation); detection bias and reporting bias; However,
attrition bias and allocation concealment was frequently unclear with
modern recommended reporting guidelines such as
CONSORT\textsuperscript{58} not being followed. We recommend using
objective methods of measuring adherence and also more than one method
of measurement, and also for the diagnosis of asthma, alongside blinding
to increase the reliability of future intervention findings.

One further limitation is not excluding interventions where the
diagnosis of asthma reported was not rigorous, for example where primary
care medical records were used to identify those with asthma despite no
record of prescribing ICS or where a physician diagnosis was given
without objective measurement of asthma\textsuperscript{59}. Future
intervention studies should ensure the children recruited have a
reliable diagnosis of asthma and objective measurements of adherence so
the true effectiveness of the interventions can be
determined\textsuperscript{60}. Therefore, this review considered the
reliability of the evidence for both the diagnosis of asthma, the
measurement of adherence and the risk of bias of the studies.

\subsection*{Conclusions}

{\label{conclusions}}

Adherence interventions in children with asthma have mixed
effectiveness. Effective studies tended to be of higher quality,
targeted both perceptual and practical adherence barriers in a tailored
manner, and used a combination of BCTs. However, due to the small number
of included studies and varying study design quality, conclusions drawn
here are preliminary.

None of the studies have explicitly addressed ICS necessity and concern
beliefs. This remains a potential area of investigation as a method for
enhancing adherence. Future interventions could consider a closer use of
the NICE guidelines including addressing patient's beliefs and the
channel by which the intervention is delivered; the increasing use of
EMD with feedback delivered in a no-blame collaborative consultation.
Future research is needed to test a PAPA-based intervention with a
rigorous study design as outlined in this review.

\section*{Funding}

{\label{funding}}

Funding by the Asthma UK Centre for Applied Research via a PhD
studentship. RH is also funded by NIHR CLAHRC North Thames. AB is an
NIHR Senior Investigator emeritus. LF is an Asthma UK Senior Clinical
Fellow.

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