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Abstract
Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV1) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of ‘normal’ (FEV1≥90% predicted) and ‘mild lung disease’ (FEV1 70%–89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.
Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.
To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled ‘Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis’, was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.
- cystic fibrosis
- imaging/CT MRI etc
- paediatric lung disaese
- respiratory measurement
- lung physiology
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Introduction
In cystic fibrosis (CF), onset and progression of lung disease in early life is now well documented.1 Structural and functional defects, which act as surrogate markers of early lung disease, are detectable soon after birth.2 3 These defects progress through preschool years, frequently in a ‘clinically silent’ fashion without symptoms or abnormalities on chest X-ray and spirometry. By school age, 60%–80% have bronchiectasis and/or gas trapping/hypoperfusion4–6 and lung function abnormalities7 8 that persist into later life. Despite advances in CF care, incremental improvement in lung function over successive birth cohorts has plateaued in childhood (figure 1). The rate of decline in adolescence and adulthood remains unchanged. These observations suggest that lung disease is established by early school age, and to improve long-term survival in the newborn screening (NBS) era, interventions must focus on preventing lung disease progression and target early lung disease.9
Changes in median FEV1 per cent predicted by age across successive birth cohorts. No further increase was achieved in comparing the last two birth cohorts and, to date, no improvement has been achieved in the subsequent rate of decline, suggesting that the foundations of lung disease are established at an earlier age.140 FEV1, forced expiratory volume in one second.
Preventing lung disease in CF requires the development of effective, evidence-based interventions. This is dependent on the ability to detect and measure early, potentially reversible changes and a thorough understanding of the pathophysiology driving disease progression. The work of several research programmes (including AREST CF,2 London CFC,10 ACFBAL,5 SHIELD CF11 and TRACK-CF12) have characterised early lung disease and provided a framework for well-designed mechanistic and intervention studies in infants and preschool children. Therapeutic trials using novel and sensitive endpoints developed by these programmes have already been conducted in older cohorts13 14 and preschool children and infants.15–18 Multiple breath washout (MBW),2 6 8 19–23 chest CT2 6 8 24 and MRI12 25 can detect early functional and structural abnormalities in children and adults despite normal forced expiratory volume in one second (FEV1) values and in the absence of other clinical features of CF disease.
Reducing current treatment burden for patients and families is a priority for the CF community.26 Incorporating novel, more sensitive approaches to monitoring and measuring outcomes for people with CF, while minimising the associated burdens for patients, families and the healthcare teams, is a major challenge.
In recognition of these issues, a meeting of experts was convened in August 2019, Perth, Western Australia, attended by representatives from paediatric and adult multidisciplinary research and clinical teams. The programme was independently designed and coordinated by the senior authorship group (PDR, SS and CEW). Vertex Pharmaceuticals sponsored the meeting.
The meeting aimed to
Describe current state-of-the-art approaches to early lung disease detection.
Discuss practicality, utility and limitations of these surrogate techniques.
Discuss priorities for future collaborative research.
Describe challenges and opportunities for integration of these novel techniques into clinical practice.
Key priorities and important unresolved questions are summarised in box 1, table 1 and the infographic in the online supplemental file 1.
Supplemental material
Summary of key priorities from the meeting
Priorities
Amend current categorisation of early lung disease.
Significant functional and structural lung disease can be detected with more sensitive techniques. ‘Normal’ and ‘mild lung disease’ categories, defined as forced expiratory volume in one second (FEV1)≥90 and 70%–89% predicted are inappropriate. Future classification and approaches must address this by using outcomes from the techniques described in this article.
Optimal detection of early lung disease to aid effective intervention.
Targeting ‘effective (treatments) in delaying or preventing the progression of lung disease in early life’ is a leading research priority for people with CF and healthcare providers.26 Our failure to change long-term rate of FEV1 decline suggests lung disease is established by early school age. Future research studies should address this concern to best inform future clinical practice.
Use the tools in well-designed intervention studies targeting early CF lung disease.
These techniques offer potential to detect and better understand the complex relationships driving early lung disease. They enable clinical trials that we must perform to describe, intervene and prevent progressive lung disease. We must advocate for and conduct well-designed intervention trials in early lung disease across all age ranges, especially young children and infants.
Be aware, assess and actively try to minimise impact on overall burden of care/treatment.
Reducing CF management burden is a top research priority.26 Understand the experiences of patients/caregivers as we push for optimised early disease detection and acceptability among the clinic population. Optimal timing/frequency of early surveillance is unclear and a balance between gaining information whilstwhile minimising impact on patients and families is necessary.
Design studies with these tests to maximise the pathophysiological insight gained.
Effective early disease detection will not be possible with a single test. Future work must harness technological advances, ensure collaboration across different sites/disciplines and prioritise studies combining these techniques to answer key questions. The complementary nature of tools should be used to better understand the underlying CF pathophysiology.
Accurate understanding of the risk of radiation with surveillance CT is critical.
Radiation concerns are limiting CT use in research studies and CF clinical care. Radiation risks need to be accurately portrayed to ensure rational decisions and recommendations can be made and radiation fears do not hamper integration into surveillance programmes. Neither the clinical and research benefits of CT nor the risk cloud interpretation of research data should be ignored.
Integration of data into CF registries and data sharing open-access platforms.
Standardisation of time points for assessment and treatment protocols will increase the insight from real-world experience and large-scale monitoring using these techniques through integration into global CF registries. Data sharing of existing and future studies on open-access platforms (including raw/control data) means potential reduction in numbers of placebo subjects.
Simplify the terminology associated with these techniques.
There is a need to simplify the language used to describe outcomes with these techniques to make terminology more straightforward for health healthcare professionals to understand.
Defining minimal clinically important difference (MCID).
Understanding what constitutes the smallest meaningful change (outside of natural variability) for each technique (ie, the MCID) remains poorly understood. Research studies must incorporate clinically relevant outcomes to aid this.
Optimise future progress through multidisciplinary collaboration.
Regular meetings to establish and maintain collaborative networks targeting advances in early disease detection in CF are essential to achieve effective integration into clinical care.
Focused questions or challenges for the future of these techniques: research and clinical (priorities for future collaborative research)
Referenced articles were chosen by authors to broadly represent the evidence base around novel techniques in the detection of CF lung disease. This did not include a standardised literature search. All included studies were deemed to be high quality based on the expertise of the author team. Several forerunner studies for these techniques also contained subjects with greater disease severity. Effort was made to include all known institutes/groups with published data in peer-reviewed journals, using these techniques within the field of CF. Descriptions of novel techniques include feasibility and practicability, sensitivity to detect early lung disease and correlates with other measures, standardisation and regulatory approvals, and use in research studies and clinical trials to date.
Current status of lung function techniques
Spirometry remains the main functional measure used in clinics and clinical trials in people with CF to detect change and assess progress. However, it is now well recognised that spirometry is not sufficiently sensitive to detect early or mild lung disease, and shows only weak correlations with structural lung damage,27 inflammation28 and variable associations with airway infection.29 Despite the universal use of spirometry, the minimal clinically important difference (MCID) remains unknown. A revised definition based on sensitive surrogates of early lung disease is needed to expedite the use of novel techniques as endpoints in future intervention studies.30
The raised volume rapid thoracoabdominal compression (RVRTC) technique can detect abnormalities in infancy and has guidelines for technical standards.31 Unfortunately, a lack of suitable reference range data for commercial equipment and problematic availability of commercial equipment and sedation limit its research and clinical utility.32 33 For this reason, RVRTC was not discussed at the meeting.
Multiple breath washout
MBW is a tidal breathing-based technique with high feasibility across infancy to adulthood.34 MBW detects ventilation inhomogeneity (or unevenness of gas mixing), most commonly reported as Lung Clearance Index (LCI).8 19 35
LCI becomes abnormal (increases) with disease onset prior to changes in spirometry indices7 8 22 and correlates strongly with structural disease on CT.2 27 The prognostic utility of preschool LCI to predict future abnormal spirometry and structural lung disease has been published by the London CFC.36 37 LCI appears more sensitive than spirometry as an indicator of acute lung function decline with respiratory events in preschool38 and school-aged children,39 and has highlighted that many do not recover to baseline values.
Consensus guidelines and technical standards have been published for preschool (and older) children,40 41 and validated commercial equipment is now available,42 43 including both Food and Drug Administration (FDA)-approved and CE-approved options. Between-subject variability has been defined in CF across several paediatric studies.21 44–46
The sensitivity of LCI to detect improvements with interventions (eg, hypertonic saline (HTS)47 48 and dornase alfa49) in preschool-aged and school-aged children with established disease, led to its endorsement as a primary outcome measure for clinical trials.50 Successful integration into large international clinical trials in preschool-aged16 and school-aged15 children used a central over-reading centre framework governing training, certification and data quality control.51 Improved LCI trajectories have been demonstrated in infants and preschoolers with early lung disease treated with HTS.16 17 Greater LCI improvements have been achieved with cystic fibrosis transmembrane conductance regulator (CFTR) modulators.52 Challenges associated with MBW include total testing time (up to 60 min in preschoolers at initial visits), additional staff training in technical aspects and feasibility of infant testing (ie, sedation). MCID for LCI remains unclear: increase/decrease in LCI of 15% is considered significant,44 46 but whether this is clinically relevant is uncertain.53
Oscillometry
Oscillometry is another tidal breathing technique which measures airway impedance of the respiratory system. It is relatively quick and feasible across all ages.54
Technical standards were published in 200355 and recently updated.56 Commercial equipment is widely available and has FDA and CE approval, and a Global Lungs Initiative task force is currently collating robust reference ranges.
The interest in oscillometry in early CF lung disease is based on its demonstrated utility in paediatric and adult asthma, correlating with disease control,57 58 and response to treatment.59 Differences between health and CF in preschool subjects have been reported60; however, oscillometry did not correlate with neutrophil elastase activity, pathogenic infection or structural lung abnormalities.61 Studies are under way in CF to assess the value of more sophisticated measures that are more sensitive to changes in wheeze/asthma detection and control, including day-to-day variability62 and within-breath fluctuations.63
Current status of imaging techniques
CT
CT is the current gold standard for demonstrating CF-related structural lung disease, characterised through indices such as bronchial wall thickening, bronchiectasis and gas trapping. CT scan abnormalities correlate with markers of lung inflammation,3 64 infection65 and with LCI.2 27
CT and MBW have similar sensitivities to detect early lung impairment.2 6 Early structural changes on CT predict later structural disease. Mucus plugging and gas trapping at age 5–6 years predicts subsequent lung function trajectory for up to 10 years, a far longer-term predictive ability than early spirometry.66 Atelectasis predicts later bronchiectasis.64 There is some evidence that radiological signs of bronchiectasis do not invariably persist in young children with CF.65 In addition, whether structural changes such as airway dilatation reflect disease-related changes or age-dependent differences in airway wall compliance remains unclear. Future intervention studies will be important to define thresholds for reversibility/improvement in structural disease indices and to improve our understanding of what these changes represent in this setting.
Since chest CT abnormalities in infants with CF were first detected,67 standardised protocols using ultralow-dose radiation and sensitive scoring systems for mild disease have been implemented within multicentre clinical trials. Notably, CT detected beneficial effects of CFTR modulator therapy among adults with mild and more severe lung disease68 69 (figure 2), as well as children with ‘normal/mild’ lung disease.70
CT images from an adult with CF, before (left) and after (right) ivacaftor treatment. There was a reduction in the degree of peribronchial wall thickening and foci of mucous plugging in the left and right lower lobes, and resolution of right middle lobe medial segmental consolidation and collapse. Reprinted with permission from the publisher of Ronan et al 68 (licence number 4895361424485). CF, cystic fibrosis.
Several challenges have been successfully navigated to develop CT as a primary outcome measure in early lung disease intervention studies.71 The limitations of historical CT scoring systems are well recognised.72 Research-based scoring systems have evolved. Initial binary scores for structural disease (eg, bronchiectasis yes/no in Brody-II)73 were shown to be insensitive in the setting of early, mild disease.10 More sensitive analyses have been developed (eg, Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA)74) which differentiate severity grades across individuals and detect progression over time in early lung disease.75 CT protocols have been standardised across multiple sites internationally76 and across different scanners. Central over-reading centre facilities and water phantoms providing standardised density readings have been developed.18 At the time of writing, objective CF-specific CT scoring systems74 77 are at varying stages of automation and do not have FDA or CE approval. Spirometer-directed CT enhances image quality78 and standardises lung volume to improve longitudinal comparison.
Challenges remain around CT use in disease detection, particularly in preschool children and infants. While free-breathing scans are available, they may underestimate airway abnormalities, and pressure-controlled scans involve anaesthesia and the associated burdens. Reliability of CT scoring (using the Brody-II Score) in infants has been questioned, and until there are validated CT scoring systems for infants, it is essential that steps be taken to minimise observer bias and to optimise intraobserver agreement.10 72 Ongoing international multicentre studies using CT PRAGMA scores will provide further insight into CT as a primary outcome measure.18 79
MRI
Proton MRI using clinical MRI scanners (1.5 T) is attractive not only as a radiation-free technique but also through the ability to derive both structural information and regional ventilation/perfusion homogeneity: so-called morphofunctional MRI.80 MRI is feasible across a broad age range but requires sedation in infants and preschoolers and is time-consuming. Awake-MRI is being explored.
Despite lower resolution, detection of early lung disease is achievable and comparable across sites.81 82 Morphofunctional CF-MRI scoring systems have been developed.83 In contrast to CT, structural changes of bronchiectasis/airway wall thickening are categorised together as differentiation is challenging. Gas trapping is identifiable and mucus plugging is easier to differentiate than in CT due to its high T2 signal.84 In a cohort of children and young people (range 0.2–21.1 years) who were almost exclusively non-newborn-screened,12 structural disease was prevalent and reported from the first year of life, with abnormalities increasing with age.12 Treatment of pulmonary exacerbation led to reduction in airway wall thickening, mucus plugging and consolidation (figure 3).81 MRI correlates strongly with LCI.12
MRI images before (left) and 1 month after (right) intravenous antibiotic treatment for pulmonary exacerbation in a 6-year-old child with CF. Improvements were observed in airway wall thickening (white arrows), mucus plugging (white arrowheads), consolidation (black arrows) and perfusion abnormalities (black arrowheads). Reprinted with permission from the American Thoracic Society. Wielpütz et al.81 CF, cystic fibrosis.
Hyperpolarised gas MRI permits visualisation and assessment of global and regional ventilation distribution, and outcomes correlate with MBW ventilation inhomogeneity.85 Ventilation defect percentage (VDP) appears to be the most promising functional MRI index.86
The role of MRI endpoints in intervention trials is emerging. Between-site stability, acceptable intrasubject variability87 and ability to detect disease progression over time25 have been demonstrated. Studies have shown detectable responses to antibiotic therapy12 81 86 and CFTR modulators.88 MRI standardisation was achieved across multiple sites89 in the Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis Study.17 In that study, LCI trajectory improved, but MRI score (based on indices of lung structure only) did not. This suggests that some treatments may improve function without improving structural changes and emphasises the value of measuring multiple outcomes in future intervention studies.
MRI imaging does present several challenges.90 Low proton density of air results in reduced signal-to-noise ratio, while numerous air–tissue interfaces create greater magnetic heterogeneity and faster signal decay (or loss). The magnitude of this effect increases at higher field strength (ie, 3 T). Additionally, this low signal target moves throughout image detection (both lung and cardiac), with higher respiratory rates and heart rates encountered at younger ages. The cost of hyperpolarised gases (eg, polarisers and access to physicists) is significant. Oxygen-enhanced proton MRI techniques have been recently developed.91 92
Future directions
Combining sensitive tools to gain insights into CF pathophysiology
Combining techniques aids interpretation of changes observed with specific techniques/indices and may provide further insight into the pathophysiological mechanisms behind early CF lung disease. This may enable targeted approaches to prevent disease progression.
LCI reflects gas mixing in the volume of lung in direct communication with the mouth. The potential for a bidirectional LCI response is well recognised in more severe disease.34 93 Imaging may provide the topographical information to explain this (eg, illustrating areas of recruited lung with impaired gas mixing in response to an intervention). Raised MRI morphology/perfusion/global scores in the setting of normal LCI12 25 (figure 4) or longitudinal worsening of gas trapping on CT despite improvements in LCI94 all reflect combined use in early disease. Several specialised MRI techniques exist,95 96 and the challenge for researchers is to use them effectively in future studies, combining/allocating resources based on varying regional expertise, cost and access issues, to advance CF understanding in early disease detection.
MRI result from four different children with CF tested at two time points (1.3–2.0 years apart) using hyperpolarised gas ventilation MRI (helium-3 ventilation MRI) and MBW. Patients were clinically stable at both time points and had normal spirometry values. Localised ventilatory defects increased in size from baseline to visit 2 (white arrows). The values for VDP and for LCI, assessed by MBW, at the time of each scan are shown alongside each image. Increases in VDP were accompanied by increases in LCI for subjects A and B, but not C and D. Adapted with permission from the American Thoracic Society, all rights reserved. Smith et al.25 Readers are encouraged to read the entire article for the correct context online (https://www.atsjournals.org/doi/pdf/10.1164/rccm.201705-0894LE). The authors, editors and the American Thoracic Society are not responsible for errors or omissions in adaptations. CF, cystic fibrosis; LCI, Lung Clearance Index; MBW, multiple breath washout; VDP, ventilatory defect percentage.
Understanding the evolution of, and relationships between, inflammation, infection and structural lung disease is critical to efforts to develop effective treatment strategies. Longitudinal research programmes have shown that combining several of these techniques with assessments of inflammation and infection is both feasible and informative. Strong correlations existed between early structural change, neutrophil elastase3 and neutrophil exocytosis97; early airway inflammation at age 5 years was associated with bronchiectasis in adolescence.64 98 The roles of specific airway organisms in structural disease onset and progression remain unclear.75 99 Future studies should address optimal study design for longitudinal monitoring of infection,100 and insights gained from animal models of CF101–105 should also be considered.
Anticipated hardware and software advances
Hardware and software advances should optimise early disease detection, enable consistent and reliable scoring, and reduce labour intensity. This may help reduce associated costs while generating an improved signal for use in intervention trials and future clinical practice.
Future MBW device design should reduce equipment-related dead space volume, for example, via main stream gas analysers,106 and optimise performance at lower flow rates. This will aid testing in infancy where age-specific technical standards are still awaited, and testing remains challenging because of the need for sedation (beyond early infancy) and lengthy testing time. Advances in MBW quality control51 107 hold promise for future automation of scoring. Prototypes of commercial devices for infant oscillometry measurement108 show promise. Advances in commercial software should soon allow intrabreath assessments of tidal volume-dependent variation in respiratory resistance and reactance.63
Advances are occurring at a rapid pace for all of the techniques discussed within this document, and particularly in the imaging domain. Advances in CT technology will improve image quality and speed of data acquisition, and aid further radiation dose reduction (while maintaining required image quality for analysis). Standardisation to address the impact of differences in hardware and software between centres will remain critical for future multicentre trials. CT is further ahead in this regard. Improvements in MRI scanner technology will provide better gradient fields (higher signal contrast and less artefact), while novel MRI research sequences include ultrashort echo times, minimise signal decay and enhance detection of smaller size anomalies (eg, mucus plugging109). Phase-resolved functional lung MRI provides dynamic regional ventilation and perfusion mapping without intravenous contrast. In younger age groups, it enables free-breathing data acquisition and a shorter examination time (≈10 min).110 Paediatric CF data using these techniques are emerging.111 112 Increased MRI field strength (eg, 3 T scanners), driven by advances in neuroimaging, is problematic for lung imaging, which operates best at lower field strength, and must be addressed by either maintaining a market for 1.5 T scanners or adapting acquisition/analysis to this ≥3 T setting.
Software advances will facilitate automated analysis and better correction for confounding factors (eg, spatially corrected density approaches to adjust for anterior–posterior distribution of lung density improving gas trapping detection). Artificial intelligence has shown significant progress in imaging–recognition tasks in recent years.113 MRI VDP is likely to evolve into more sophisticated indices for quantitative assessment, improving its sensitivity and utility.
Interpretation of radiation risk
Concerns about radiation limit the use of surveillance CT in research studies and CF clinical care, and risks must be interpreted in the correct context. Detection of parenchymal pathology is felt to be less important than airways in CF, enabling lower dose protocols and radiation reduction. Estimated exposure of annual surveillance scans from some centres is low: ≈2 mSv by age 6 years, which is less than the average annual background radiation exposure across US cities (3.1 mSv/year).114 Recent modelling data based on biennial CT scan until the age of 50 years found the risk to be 0.2%, lower than the 0.7% from background radiation.115 CF survival may reach 60+ years, so future research needs to balance the apparently low risk of radiation exposure from a chest CT with clinical utility and subsequent action.116 117
Opportunities with data registries
CF registries offer a unique opportunity to learn from the increasing research and clinical use of these techniques. Global CF registries now capture data on almost 100 000 individuals with CF and have provided valuable insight into CF epidemiology, pathogenesis and prognosis (eg, USA,118 Canada,119 UK120 and Australia121). These large-scale platforms could collate results of newer techniques such as LCI, CT and MRI from clinical experience. Integration of outcome markers using these novel techniques into data registries will be aided by standardisation of time points for assessment and treatment protocols. This could allow investigations into effects of interventions compared with defined control groups.122 Data sharing of existing and future research studies on open-access platforms, such as Project Data Sphere used in cancer trials, could have numerous benefits for CF if established.123 Making control data freely available has the potential to reduce placebo group numbers, a particular challenge for studies performed in young age groups, and those using techniques with ionising radiation.
Multicentre collaboration
Multicentre collaboration, including different age ranges and techniques, is vital to ensure future research studies are appropriately designed to address the key questions remaining for early disease detection and monitoring (table 1). Observational studies that characterise natural disease progression21 and adequately powered intervention studies16 that demonstrate disease reversal, or prevention of progression, will be important. Collectively, these studies will determine the optimal age and stage of disease for intervention. Comparisons of novel techniques with existing clinical monitoring tools and age-appropriate quality of life measures124 are required.
Incorporating new techniques into clinical practice
Are these tests ready for clinical use?
Prerequisites for clinical utility include widespread availability, feasibility, repeatability and sensitivity, using standardised protocols and equipment. Many of the tests discussed earlier satisfy several of these fundamental criteria. Questions remain, however, regarding optimal choice, frequency and timing at different clinical stages, and how to interpret results to guide clinical management.
Clinical experience with LCI is emerging,20 125 as well as the challenges faced when incorporating into busy clinics and younger preschool age groups.126 The optimal age to start and frequency for MBW monitoring have not been defined, and younger age groups such as preschoolers present specific challenges.126 Use of LCI at annual review in young children or those with normal FEV1 has begun to appear in management recommendations.127–129 Before clinical use can be universally recommended, further studies are needed to define clinically meaningful change in acute and chronic CF care (particularly exacerbations), ways to reduce testing time and guidance around the use of LCI in clinical disease surveillance.
CF clinical care already uses CT: 75% ‘used CT scans regularly’ in a recent questionnaire survey across 25 participating CF centres in Europe and Australia.117 While recent studies have illustrated the utility of CT in clinical decision making116 117 and initiating management changes,117 whether regular CT surveillance improves health outcomes is unclear. Before routine CT surveillance can be recommended, clinical guidelines are required to address optimal timing and frequency of surveillance. Biennially performed CT has been recommended by some authors.130
MRI and oscillometry are still not sufficiently validated for integration into routine CF clinical care. MRI is resource intensive and expensive, and widescale use across clinics might not be feasible despite the lack of ionising radiation. Protocols enabling free-breathing data acquisition and a shorter examination time may address concerns regarding need for sedation in younger children. Oscillometry is less expensive and more feasible within busy clinics than MBW, but what the data tell us about CF disease and progression is uncertain.
Organisational challenges
Implementing novel surveillance techniques into clinical practice will be largely governed by the size of the clinic population (influencing frequency and timing of measures). Physical and staff resources available to accommodate procedures (including training and education) are important factors. Implementation is contingent on robust partnerships with radiology, anaesthetists, respiratory scientists, healthcare professionals, patients and families. Prior engagement with stakeholders, including local regulatory bodies, is recommended to navigate financial, technological and logistic issues. CF infection control requirements are a primary consideration in the use of technical equipment and associated clinical areas. Time constraints placed around testing may detrimentally affect feasibility126 131 as well as need for general anaesthesia or sedation.
Impact on patients and families
The impact these measures have on perceptions of health, burden of care26 and the psychosocial implications of disease detection must be addressed. Positive attitudes from parents towards infants recruited at NBS132 and high adherence rates reported in recent infant17 and preschool16 intervention studies are encouraging. The generalisability of intervention trial settings to clinical practice is uncertain. Parental expectations of clinical benefit associated with enhanced surveillance techniques132 133 and available therapies require careful management.134 Discussion of limitations, roles and expectations of these techniques to avoid therapeutic misconceptions is important. Parental uncertainty about novel techniques and anxiety related to perceived risks and safety,132 134 particularly around sedation for CT or MRI, highlight the importance of well-designed information resources and the role of CF psychosocial teams. They ensure patients and/or families are prepared and supported. Impacts on child and parent emotional well-being should be anticipated.133 134 Policies that prevent and manage procedural distress should be incorporated into trials and clinical practice.135–137 Routine screening of mental health and assessment of coping skills in caregivers (and children) from diagnosis,138 with interventions that promote psychological adjustment and effective coping, are suggested.137 139
Conclusions
The prevention of early lung disease is a priority for researchers, clinicians, patients with CF and their families.30 We currently possess tools and expertise that may be used to assess early lung disease progression. Future work must better define how and when to incorporate different testing modalities, the parameters to use, and the frequency of testing for clinical use and research outcomes. We must advocate for properly designed, rigorously conducted interventional studies in mild disease, especially in young children, and advise against regulatory submissions of safety data or extrapolated efficacy data from older age groups only. Trials in young subjects with CF and early lung disease in general are poorly served by current regulatory endpoints, which should instead be based on the techniques described in this article. Advances in understanding around the evolution of early CF lung disease present an exciting opportunity to prevent structural damage and to slow the ongoing decline in lung function that we have failed to prevent to date. Intensification of monitoring in this setting is justified if the correct balance is achieved between burden, gaining useful clinical information and creating opportunity to intervene and improve outcomes. In an era of wider access to highly effective CFTR modulator therapies, the ability to detect the evolution of early disease and its response to intervention will be of increasing importance.
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References
Supplementary materials
Supplementary Data
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Footnotes
KJB and TAD are joint first authors.
Twitter @ktjbay, @DrPLungResearch
KJB and TAD contributed equally.
Correction notice This article has been corrected since it was published Online First. Minor changes have been made to the author names.
Contributors All authors made substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data. Drafting the work was principally performed by KJB, TAD, TR, SS, CEW and PDR. All authors revised it critically for important intellectual content. Final approval of the version published was provided by all authors. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The Shaping Imaging and Functional Testing for early detection of lung damage in cystic fibrosis (SHIFT) meeting was held as a satellite meeting to the 2019 Australasian Cystic Fibrosis Conference and was sponsored by Vertex Pharmaceuticals Ltd. The rules of engagement were that Vertex did not have any input into the content or how the meeting was run, but they did support the venue, communication for the meeting, and where required, transportation costs and honoraria. Details regarding renumerations received across the author group are found in the authors’ declaration forms attached to the manuscript submission. PDR, CEW and SS were members of the steering committee that organised the meeting.
Competing interests TR reports personal fees from Vertex Pharmaceuticals during the conduct of the study; in addition, TR has a patent PCT/AU2016/000079 issued. JCD reports others from Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Galapagos NV, ImevaX GmbH, Nivalis Therapeutics, Inc., ProQR Therapeutics III B.V., Proteostasis Therapeutics, Inc., Raptor Pharmaceuticals, Inc, Vertex Pharmaceuticals (Europe) Limited, Enterprise, Novartis, Pulmocide and Flatley; grants from CF Trust; and others from Teva, outside the submitted work. JSE reports grants from Ionis and the European Commission; personal fees and others from Vertex, during the conduct of the study. MM reports grants from the German Federal Ministry of Education and Research and Einstein Foundation Berlin, during the conduct of the study; personal fees and others from Boehringer Ingelheim and Vertex Pharmaceuticals; personal fees from Arrowhead Pharmaceuticals, Santhera, Galapagos, Sterna Biologicals, Enterprise Therapeutics and Antabio, outside the submitted work. FR reports non-financial support from Vertex during the conduct of the study and acts as a consultant to Vertex Pharmaceuticals, who was the sponsor of this meeting. ARS reports grants from Vertex and personal fees from Novartis, Teva and Vertex, outside the submitted work; and patent issued: 'Alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof'. SS reports a patent licensed to Thirona, and a patent licensed to Resonance Health Ltd and Institutional reimbursement from Vertex Pharmaceuticals (Australia) Pty Ltd. for Steering Committee Member duties organising SHIFT at the Australasian Cystic Fibrosis Conference 2019, Perth. CEW reports institutional reimbursement from Vertex Pharmaceuticals (Australia) P/L for Steering Committee Member duties organising SHIFT at the Australasian Cystic Fibrosis Conference 2019, Perth; income on a per patient basis derived from Pharmaceutical Studies - Vertex Pharmaceuticals Inc., and Boehringer-Ingelheim; research grant from Novo Nordisk Pharmaceuticals P/L- CF-IDEA Study; other reimbursements from Vertex Pharmaceuticals P/L honorarium to attend CF International Advisory Board Meeting in February 2014, Vertex Pharmaceuticals P/L honorarium to attend CF Medical Advisory Board Meeting in Adelaide in April 2014, Novartis Pharmaceuticals P/L honorarium to present symposium at National Pediatric Congress in Lebanon in May 2014, European CF Conference in Gothenburg June 2014 Vertex Pharmaceuticals P/L return travel and honorarium for lecture and discussions, North American CF Conference Georgia October 2014 DKBmed, LLC honorarium to present symposium, Vertex Pharmaceuticals P/L honorarium to present as speaker in an educational meeting series in Brisbane and Sydney in April 2015, Vertex Pharmaceuticals P/L honorarium to attend the Vertex Steering Committee Meetings re VX15-770-123 Study in 2014, Vertex Pharmaceuticals P/L honorarium for Vertex Medical Advisory Board- Innovative endpoints in CF in August 2015, The University of Miami honorarium for meeting attendance in 2015, Thorax honorarium for associate editor duties Q3/Q4 2015, BMJ honorarium for work as reviewer, Vertex Pharmaceuticals 2015 Chicago return flight and accommodation as investigator in Lumacaftor study, Vertex Pharmaceuticals 2015–2017 honorarium as speaker at Vertex sponsored educational meeting series in Australia, Vertex Pharmaceuticals 2016 Phoenix return flight and accommodation as investigator in Next Gen study, Vertex Pharmaceuticals December 2016 honoraria as speaker at Vertex sponsored educational meeting in Liverpool, UK DKBmed eCF Review Issue honoraria in January 2017, Vertex Pharmaceuticals–March 2017 honoraria as speaker at TSANZ meeting Vertex Pharmaceuticals Inc. 2014–2018, honorarium for acting as consultant on the Vertex Orkambi 6-11 HTA Advisory Board, the Global Pediatric Advisory Committee, the Global Medical Advisory Board, and the VIA Grants Committee; Gilead Sciences Ltd. honorarium for meeting attendance on CF imaging; Honorarium for In Vivo Academy Limited for webcast meeting attendance at ECFC–2018; Vertex Pharmaceuticals P/L honorarium to present as speaker in an educational meeting at ECFC in Belgrade–2018; Vertex Pharmaceuticals Inc. honorarium to attend Next Gen Early Lifecycle Management Plan–London–2018; Vertex Pharmaceuticals P/L to act as consultant and to render such services in the form of documents, advice, meetings and conferences during the period October 2018; present Vertex Pharmaceuticals P/L to attend the EU Real World Evidence Steering Committee in Amsterdam–2019 Current Board Positions–International Advisory Board Vertex Pharmaceuticals P/L Deputy Editor Thorax /Associate Editor Respirology. PDR reports institutional reimbursement from Vertex Pharmaceuticals (Australia) Pty. Ltd for Steering Committee Member duties organising SHIFT at the Australasian Cystic Fibrosis Conference 2019, Perth.
Provenance and peer review Not commissioned; externally peer reviewed.