Exploring the potential of cardiopulmonary exercise testing (CPET) for tailored pulmonary rehabilitation in people with interstitial lung disease (ILD): A systematic review protocol

Rationale

Interstitial lung disease (ILD) is a heterogeneous group of approximately 200 chronic lung conditions, which are associated with lung parenchymal fibrosis and/or interstitial inflammation¹. Consequently, respiratory failure is the primary cause of mortality in people with ILD². According to 2017 figures, the median age-standardised incidence rates (ASIR) of ILD in United Kingdom (UK) men was 10.92 per 100,000, and 6.7 per 100,000 for UK women³. From the period between 2001 and 2017, the ASIR has risen by 21.27% for UK men and 25.39% for UK women³. In addition, the median age-standardised death rates indicated that ILD related mortality was 2.04 (IQR 1.13–2.71) per 100 000 population for men and 1.02 (0.68–1.37) per 100,000 population for women³. Unfortunately, ILD are chronic conditions that cannot be cured, therefore maintaining lung function, general function, and quality of life (QoL) of people with ILD (pwILD) is a key focus for patients and clinicians alike⁴.

A joint statement produced by the American Thoracic Society (ATS) and European Respiratory Society (ERS) recommends regular exercise training and pulmonary rehabilitation (PR) to enhance cardiorespiratory health⁵, whereby exercise is acknowledged as a planned, structured, and repetitive form of physical activity which is performed for the improvement or maintenance of physical fitness⁶. International guidelines highlight that exercise training is regarded as a cornerstone of PR⁵. However, individual patient responses to exercise training are highly variable and a ‘one size fits all’ training approach does not benefit every pwILD⁷, thus placing the onus on to effective PR design.

Pulmonary rehabilitation is an intervention which is developed following comprehensive diagnostic evaluation by a multidisciplinary team; the aim is to utilise these assessment outcomes to establish a patient-centred therapeutic program which consists of exercise and patient education to support behaviour change, but also improve physical and mental health for people with chronic respiratory diseases⁸. The British Thoracic Society (BTS) explicitly recommends that PR should be offered to symptomatic individuals with chronic respiratory disease, including pwILD⁸. Therefore, National Health Service in the United Kingdom, alongside the National Respiratory Audit Programme (NRAP) are aiming to drive forward the quality of PR services⁹.

A 2021 Cochrane review of PR in pwILD has found “moderate-certainty” evidence associated with enhanced functional exercise capacity (measured by the six-minute walk test, 6MWT) and “low-certainty” evidence that suggests that PR in pwILD may improve maximum exercise capacity (WR_peak) and dyspnoea¹⁰. These benefits are postulated to be sustained in the longer term (e.g. 12 months duration) and there is also no evidence that adverse events were found in the pwILD¹¹. Therefore, PR is not only useful for enhancing QoL in pwILD, but functional capacity as well¹¹. However, no PR guidelines have been developed specifically for pwILD at present, despite them being available for other chronic respiratory diseases such as COPD¹². Therefore, the James Lind Alliance has made ‘best exercise program for people with Pulmonary Fibrosis’ part of their top ten research priorities¹³.

The main challenge for development of PR guidelines in ILD is related to the breath of pathophysiological impairments that occur across the different ILD subgroups, which may lead to variation in exercise tolerance and capacity¹⁴. Restrictions in exercise tolerance may be due to ventilation/perfusion (V/Q) mismatch, which occurs when either airflow or blood flow in the lungs is impaired and abnormal ventilatory mechanics can occur at different points for pwILD¹⁴. Therefore, pwILD may often require more ventilatory load and capacity to sustain exercise, whilst also attempting to combat muscle fatigue, commonly because of poor blood oxygenation¹⁴; this may lower ATP, increase lactate and cause a rise in VCO₂¹¹. Gas exchange insufficiency, central haemodynamic impairment and muscle deconditioning are prevalent in the ILD population¹⁴. Therefore a tailored approach to exercise prescription may provide enhanced physical function outcomes, as tailoring could account for these mechanisms of exercise intolerance in chronic lung diseases¹⁵. However, due to the complex characteristics of ILD, a review of the methods used for tailored exercise prescription is required, before comprehensive guidelines in this population can be developed.

The BTS Clinical Statement on pulmonary rehabilitation states that a validated exercise test should be conducted as a core component of PR programmes to inform tailored prescription⁸. Within ILD management, field tests such as 6-minute walk distance (6MWD)^16–18 and the incremental shuttle walk test (ISWT)¹⁹ are often used as a functional outcome because they are valid, easy to implement and cost-effective^16–19. However, field tests cannot highlight the full spectrum of pathophysiological mechanisms which limit exercise tolerance, and safety issues such as ischemia or arrhythmias cannot be easily detected²⁰. Both aspects are of upmost importance when looking to prescribe exercise in the ILD population, due to the aforementioned physiological impairments¹⁴. Therefore, the focus of this systematic review is to explore the potential utility of CPET to provide the precision required for tailored exercise prescription in ILD.

Tailored exercise via CPET has been earmarked as the future of PR, whereby a comprehensive evaluation of pathophysiological systems serves to indicate responses to exercise, and therefore these values could support effective PR programming¹⁴. Evidence suggests that CPET is now the gold standard for the causal evaluation of exercise intolerance in patients with long term pulmonary conditions²¹. It has been demonstrated that CPET is a safe and valuable method for the comprehensive evaluation of cardiac, pulmonary and muscle function²¹, whilst also recognising physiological factors limiting exercise such as dyspnoea²².

Exercise prescription methods which are tailored to the cardiovascular, pulmonary, and peripheral muscle metabolic limitations of the individual patient have the potential to be the cornerstone of tailored PR¹⁴. Recent evidence suggests that tailored, moderate-intensity continuous aerobic exercise (at 60% maximum heart rate; HR_max) and high-intensity interval training (at 80% HR_max) is beneficial in pwILD for improving WR_peak and dysponea²³. Moreover, tailored exercise training can enhance antioxidant buffering capacity in people with idiopathic pulmonary fibrosis (IPF), which may corelate with enhanced muscle fatigue resilience²⁴. This clearly demonstrates the functional and physiological value PR can have when using tailored approaches.

However, for widespread success of tailored PR programmes in ILD, implementation of exercise prescription principles (e.g. specificity, frequency, intensity, timing, type, overload, progression, adaptation, and reversibility) should be followed and reported accordingly⁵. At present, it is not clear if this is currently done for pwILD; the current systematic review helps provide an overview of practice regarding the components of exercise prescription in this population.

There is also a need to develop a valid, reliable, and consistent method for personalising PR based on CPET outcome measures. Several metrics could be used (e.g. VO_2peak or heart rate), but it is unclear what metrics are currently used and how they are implemented. This systematic review will seek to address this, with the intention of highlighting the CPET-derived exercise prescription variables that have been used to tailor PR for pwILD.

Objectives

This review aims to identify which cardiorespiratory variables, and intensities, derived from CPET can be used to personalise PR for pwILD.

Eligibility criteria

The PRISMA-P has been used to guide this systematic review protocol²⁵. Eligibility for inclusion in this review include the following elements of the PICOS framework (Table 1); conference abstracts will be excluded; articles which are not published in English, unless an English translation is available, will be excluded; there will be no restriction on publication date, or location.

Population

People of all ages, sexes and ethnic groups that have been diagnosed with any ILD subtype.

Intervention

Tailored PR or exercise programmes, which have used CPET derived values. Articles that only describe ‘physical activity’ interventions, and not ‘exercise training’ or ‘pulmonary rehabilitation’, will be excluded. Single or acute bouts of exercise will not classify as exercise training.

Comparison

Outcomes of PR regimens against group baselines, and where possible, against control groups as well will be compared.

Outcomes

Outcomes will be derived from CPET values. It is anticipated this may include, but will not be limited to:

Study designs

All quantitative study designs will be included; for instance, RCT’s, single cohort studies and case studies. Only full-text, original articles will be included.

Information sources

Electronic searches will be conducted using Ovid® (Ovid Technologies Inc., New York, NY, USA), incorporating Ovid MEDLINE® (US National Library of Medicine, Bethesda, MD, USA), Ovid EmbaseTM (Elsevier Inc., Philadelphia, PA, USA), EBSCO databases CINAHL Ultimate and SPORTDiscus (EBSCO Information Services, MA, USA) plus CENTRAL and the Cochrane Library (John Wiley and Sons Ltd, Hoboken, NJ, USA) will all be searched up to January 2025.

Search strategy

The search strategy is available at OSFHOME: Exploring the potential of cardiopulmonary exercise testing (CPET) for individualised pulmonary rehabilitation in people with interstitial lung disease (ILD): A systematic review protocol: Search_Strategy.docx. Available at: https://doi.org/10.17605/OSF.IO/43N29.

Following completion of the Ovid MEDLINE® strategy, specific syntax and subject headings will be created for all Ovid, EBSCO and Cochrane database searches.

Data management

Independent data extraction will take place using data extraction forms developed for the study. Data to be extracted and included in the table of ‘overview of included studies’ will include author and year, purpose of study, setting, country, sample size, participant demographic and clinical diagnosis, treatment types, study design, primary outcome measures, losses and exclusion of participants. EndNote© 20²⁶ (Clarivate, London, UK) will be utilised for reference storage.

Selection process

A screen of the initial search results will be performed by title and abstract for eligibility and inclusion. The search results will be checked by a single reviewer (BB), then an experienced second reviewer (TBC) will perform a check of 10%, then a third reviewer (TBC) will check for differences and achieve a consensus through discussion with the reviewers.

Data collection process

Data will be collected by a single reviewer (BB) using a data extraction form. A random double data extraction (10%) check will then be performed by a second reviewer (TBC). Any differences will be highlighted by a third reviewer (TBC), then a discussion with the reviewers will be performed to achieve a consensus. Any missing data will be requested from the study authors, before removal from the review, if no reply is provided.

Data items

The PICOS inclusion and exclusion criteria (Table 1) will be used by (BB and TBC) to as a framework to collate and review all the full text articles which are potentially relevant for the review. If disagreement occurs between the reviewers, then a discussion with the third reviewer (TBC) will be conducted to reach consensus. Outcomes will be derived from CPET values. We anticipate that the main outcomes will be displayed in a summary of findings table using GRADEpro²⁷.

Risk of bias in individual studies

Quality assessment of the included studies will be performed by two reviewers (BB; TBC) using the Critical Appraisal Skills Program (CASP) checklists for single cohort studies²⁸ and randomised controlled studies²⁹, thus accounting for the anticipated variances in study designs for this review. A third reviewer (TBC) would then confirm the results and lead the discussion towards consensus of the included studies. The CASP checklist items are to be marked “Y” (Yes) if well described, “N” (No) if inadequate, and unclear items with a “U” (Unclear).

Reporting quality

The Consensus on Exercise Reporting Template (CERT) assessment form will be used to check the reporting of exercise programme domains³⁰. This would support researchers to develop effective exercise interventions, that are well constructed and reproduceable. Using the CERT would also help policymakers with making exercise recommendations and guide peer reviewers in manuscripts evaluation³⁰.

Synthesis

All analyses will be performed using Review Manager³¹.

Meta-bias(es)

Reporting bias would be explored by examining if the protocol was published prior to study participant recruitment. A Clinical Trial Register at the International Clinical Trials Registry Platform of the World Health Organisation screen would also be conducted. Selective outcome reporting bias would be evaluated by comparing the fixed effect estimate against the random effects model to examine the potential for sample bias. If this occurs, then a random effects estimate would be advantageous, when compared against a fixed effect estimate. Reporting bias could also be examined by funnel plots if ≥10 studies are identified.

Confidence in cumulative evidence

The GRADE tool³³ would be used to assess the evidence for the primary outcome of CPET values. Analyses and presentation of the results would be stated in a 'Summary of findings' table, generated using GRADEpro GDT²⁷ software.