Ehlers-Danlos Syndrome (EDS) is a group of hereditary connective tissue disorders characterized by multisystem manifestations involving musculoskeletal and nonmusculoskeletal domains [1]. Currently, the International Classification of EDS and related disorders includes 14 subtypes based on a set of clinical criteria, with the most common subtype being hypermobile EDS (hEDS), which comprises 80% to 90% of EDS cases [1-3]. Patients who present with symptomatic generalized joint hypermobility and chronic pain but do not meet the International 2017 classification criteria are classified as having generalized hypermobility spectrum disorder (G-HSD) [3]. The clinical manifestations of the disease vary according to the EDS subtype, and our understanding of this disorder has evolved to recognize multisystem manifestations beyond the musculoskeletal system, including gastrointestinal, neurological, cardiovascular, and respiratory involvement [1]. These manifestations arise from abnormal collagen or proteins that bind collagen that affect the connective tissue throughout the body [1]. Given the multisystem nature of hEDS and G-HSD, several symptoms such as pain and fatigue may contribute to reduced health-related quality of life (HRQL), physical deconditioning, anxiety, and depression [4-8].

Our research group and others have recently highlighted that respiratory manifestations are common in hEDS and G-HSD and include, but are not limited to, dyspnea, cough, asthma, and respiratory muscle weakness [2,9]. The collagen abnormalities lead to impairments throughout the respiratory system, which may contribute to the respiratory abnormalities observed in this population [2,10]. In individuals with hEDS, the prevalence of dyspnea is estimated to be approximately 50% [11]. Dyspnea has been described in a few studies on individuals with G-HSD, but its prevalence and determinants have not been well characterized [12]. A study reported that up to 26% of the patients with G-HSD presented with cardiorespiratory manifestations such as dyspnea, palpitations, and chest pain, which were commonly attributed to autonomic dysfunction [13].

Respiratory symptoms in EDS and G-HSD have also been associated with worse outcomes such as lower physical activity levels and function. Individuals with EDS or G-HSD experienced increased dyspnea while walking on a flat level compared with healthy controls [12]. Furthermore, a study investigating physical activity levels between patients with hEDS or G-HSD with autonomic dysfunction and those without autonomic dysfunction observed that autonomic dysfunction was associated with exercise intolerance, which is often attributed to increased symptoms of dyspnea and chest pain [14]. Postural orthostatic tachycardia syndrome, a more severe form of autonomic dysfunction, has also been observed to be associated with dyspnea, chest pain, and impairments in HRQL [15,16]. Thus, respiratory manifestations in individuals with hEDS or G-HSD have important consequences on exercise tolerance, HRQL, and functional abilities.

Functional impairments in respiratory muscle weakness occur in >75% of individuals with hEDS and can result in dyspnea and a restrictive pattern of ventilation [11]. The diaphragm is the main respiratory muscle, and alterations in collagen can lead to impairments in the respiratory muscle structure and function [17]. Respiratory muscle weakness has also been associated with lower vital capacity, which may contribute to dyspnea [18,19]. Thus, strengthening the respiratory muscles through modalities such as inspiratory muscle training (IMT) may improve dyspnea and pulmonary function [20].

Some individuals with hEDS or G-HSD have been observed to have chest wall deformities and increased rates of asthmatic symptoms, which can contribute to dyspnea and peripheral airway abnormalities [12,21,22]. There is also an increased tendency for dynamic airway collapse despite normal chest imaging, which highlights altered lung mechanics, including airway pressures and lung volumes [12]. Furthermore, deconditioning has been described as a contributor to low physical activity levels in the population with EDS or G-HSD as a consequence of increased joint laxity, pain, and peripheral muscle weakness [23]. Physical deconditioning may further exacerbate dyspnea and contribute to low exercise tolerance [23]. In conditions such as chronic obstructive pulmonary disease (COPD), cortical neural activity in the prefrontal cortex (PFC) has been shown to be associated with dyspnea and exercise intolerance and may be another contributor to dyspnea in hEDS or G-HSD [24,25]. Modalities such as functional near-infrared spectroscopy (fNIRS) have been used to assess PFC activity in individuals experiencing dyspnea during exercise testing [24]. Taken together, respiratory muscle weakness, peripheral airway changes, physical deconditioning, and autonomic dysfunction may contribute to the multifactorial nature of dyspnea in hEDS or G-HSD. These factors can be evaluated clinically and may help us understand the mechanisms that contribute to dyspnea and, importantly, tailor effective respiratory management strategies.

IMT has been established as an effective intervention for improving respiratory muscle structure and function in populations with chronic lung diseases [26,27]. A study observed that among 104 individuals with hEDS, 80 (77%) individuals had respiratory muscle weakness [11]. After 6 weeks of IMT, respiratory muscle strength measured with sniff nasal inspiratory pressure improved by 20% (pre-IMT intervention: mean 41, SD 17 cm H₂O vs post-IMT measurement: mean 49, SD 18 cm H₂O; P<.001) in patients with hEDS. Furthermore, the 6-minute walk distance improved by 13% (pre-IMT measurement: mean 455, SD 107 m vs post-IMT measurement: mean 515, SD 127 m; P=.003) along with forced expiratory volume in 1 second by 10% (pre-IMT measurement: mean 94%, SD 14% vs post-IMT measurement: mean 103%, SD 11%; P=.01). Thus, IMT may be an effective intervention for improving respiratory muscle strength, lung function, and exercise capacity in patients with hEDS or G-HSD.

Physical rehabilitation involving whole-body exercises such as aerobic and strength training has been shown to improve dyspnea in healthy populations and populations with chronic lung diseases such as COPD and idiopathic pulmonary fibrosis [28-31]. In a meta-analysis of 14 randomized controlled trials (RCTs), resistance training and endurance training were associated with improved dyspnea tolerance during exercise training, along with resting dyspnea levels, in patients with COPD [30]. This is often attributed to improved physical fitness owing to exercise training, which increases the efficiency of the muscles and decreases the level of ventilatory demand [30]. Unlike other populations, research on the effects of exercise training on individuals with hEDS or G-HSD is in its early stages, with only 5 RCTs performed in this area to date [32]. Following rehabilitation, in patients with hEDS or G-HSD, improvements have been observed in exercise capacity, muscle strength, mood, HRQL, and performance of daily activities [32].

Although the IMT RCT highlighted the safety and feasibility of IMT in hEDS, the study did not evaluate the mechanisms of dyspnea or assess diaphragm structure and function [11]. Furthermore, physical activity and other concurrent training, which may provide synergistic beneficial effects on respiratory symptoms and exercise capacity, were not considered. Several studies on chronic lung disease have demonstrated that IMT in combination with whole-body exercises, such as aerobic exercise, offers synergistic benefits on respiratory muscle strength and endurance and exercise capacity in comparison with whole-body exercises alone [23,33,34]. IMT alone has been shown to be an effective intervention in populations with asthma, populations with COPD, and populations with interstitial lung disease for improving maximal inspiratory pressure (MIP), respiratory muscle endurance, and diaphragm function [26,27,35] and thus may be an effective strategy in the population with hEDS or G-HSD.

The efficacy of both IMT and standard-of-care rehabilitation in ameliorating dyspnea and improving aerobic capacity and respiratory muscle structure and function in the population with hEDS or G-HSD has not been investigated to date. It is also unclear whether IMT in combination with standard-of-care rehabilitation is a feasible intervention, specifically for the population with hEDS or G-HSD, given the increased comorbidities. Furthermore, the efficacy of IMT has only been evaluated in hEDS and yet to be studied in G-HSD. This study aims to address these gaps.

The aims of this study are (1) to compare respiratory muscle strength and patient-reported outcome measures (PROMs) between individuals with hEDS or G-HSD and healthy, age- and sex-matched controls, as well as evaluate the main contributors to dyspnea in individuals with hEDS or G-HSD, and (2) to assess the feasibility of an RCT of IMT and standard-of-care rehabilitation (aerobic, resistance, neuromuscular stabilization, and balance and proprioception exercises) for improving respiratory muscle strength, exercise capacity, and PROMs compared with standard-of-care rehabilitation in hEDS or G-HSD.

We hypothesize that (1) individuals with hEDS or G-HSD will have lower respiratory muscle strength, higher peripheral airway resistance, lower HRQL, and higher anxiety and depression levels than age- and sex-matched healthy controls and that (2) the delivery of IMT and standard-of-care rehabilitation will be feasible and result in a significant improvement in respiratory muscle strength (MIP) over an 8-week period.

Participants with hEDS or G-HSD will complete assessments at baseline (T₀; Table 1) and will be randomized into the intervention arm (IMT and standard-of-care rehabilitation) or usual care group (standard-of-care rehabilitation). The standard-of-care rehabilitation at the GoodHope EDS Clinic at Toronto General Hospital comprises active exercise training involving aerobic, resistance, neuromuscular stabilization, and balance and proprioception exercises, and is a part of the GoodHope Exercise and Rehabilitation Program (GEAR) [36].

Age- and sex-matched healthy controls will undergo the same T₀ assessments as those that the EDS and G-HSD intervention and usual care groups will undergo. The respiratory muscle structure and function, dyspnea, exercise capacity, and collected PROMs will be compared. Only the participants with hEDS or G-HSD (intervention and usual care groups) will repeat the T₀ assessments after 8 weeks, as described in the subsequent section on assessments.

Ethics approval has been obtained from the research ethics board at the University Health Network (ID: 20-6346.0) and University of Toronto (ID: 42667). The study has been registered at ClinicalTrial.gov (NCT04972565).

Written informed consent will be obtained from all participants before the commencement of any research activities. The Standard Protocol Items: Recommendations for Interventional Trials, the CONSORT (Consolidated Standards of Reporting Trials) statement, and the Consensus on Exercise Reporting Template will be used [37-39]. Refer to Figure 1 for the CONSORT flow diagram.

Participants with hEDS or G-HSD will be recruited from the GEAR program at Toronto General Hospital, which is a major teaching hospital in Toronto, Canada. The GEAR program evaluates approximately 12 new participants per month. Potential participants are screened for study eligibility by exercise professionals who are part of the GEAR program. The research team will confirm the eligibility criteria, discuss study participation, and obtain consent among interested participants. The study flow of participants is shown in Figure 1.

The sample will comprise adult individuals (aged ≥18 years) diagnosed with hEDS or G-HSD by the EDS medical team at Toronto General Hospital based on the 2017 diagnostic criteria [3]. Participants will be included if they have started their participation in the GEAR program within 4 weeks.

The following exclusion criteria will be applied:

Healthy adults (aged ≥18 years) will be age- and sex-matched with the participants with EDS and G-HSD. Individuals will be excluded from the study if they meet the following criteria:

At T₀, the participants with hEDS and G-HSD will undergo pulmonary function tests (PFTs), cardiopulmonary exercise test (CPET) with fNIRS on the PFC, PROMs, and diaphragm ultrasound. The same assessments will be performed for healthy controls. Please refer to Table 1 for a detailed list of T₀ measurements. At 4 weeks, respiratory muscle endurance assessment will be repeated for the participants with hEDS and G-HSD. All T₀ assessments, including PFTs, CPET, PROMs, and respiratory muscle endurance assessment, will be repeated at 8 weeks for the participants with hEDS and G-HSD.

The following tests will be used to assess the primary and secondary outcome measures in the PFT laboratory at Toronto General Hospital.

Standard anthropometric measures will be captured for all the participants. Height, weight, waist circumference, and BMI information will be collected for the participants with hEDS or G-HSD from the electronic patient charts. The same measures will be collected for healthy controls during the T₀ assessments.

We will abstract standard GEAR program measures from the medical charts for all the participants with hEDS or G-HSD: 6-minute walk distance, lower extremity function (5-repetition sit-to-stand test), hand-grip strength, Bristol questionnaire, and Godin Leisure-Time Exercise scale. The Beighton score [68], Charlson comorbidity index [69], and medications such as opioids that can impact dyspnea will be abstracted from chart review.

We will abstract information on demographics such as age, ethnicity, sex, employment status, education level, and lifestyle factors (eg, smoking status) from the medical charts for the participants with hEDS or G-HSD. Demographic data will be collected from healthy controls via a demographic survey.

After T₀ assessments, the participants will be randomly allocated to the intervention or usual care group using a 1:1 ratio stratified by hEDS or G-HSD. The allocation of the participants to their groups will be randomized (blocks of 2 to 4) using shuffled, opaque envelopes by a biostatistician. The study participants and the research team and coordinator supervising the IMT will be aware of the group assignments.

This study will help characterize the multifactorial nature of dyspnea experienced by individuals with hEDS and G-HSD. Given the known impairments in respiratory muscle strength in this population, this study will allow us to assess the synergistic effects of IMT and standard-of-care rehabilitation on dyspnea, PROMs, and exercise capacity, which have not been previously characterized. The findings of this study will inform the feasibility of a larger study using IMT and standard-of-care rehabilitation that will be appropriately powered to assess the effects of IMT on PROMs and clinical outcomes. Furthermore, this study has the potential to inform our understanding of the mechanistic effects that IMT may have on diaphragm structure and function, lung physiology, and neurocognitive adaptations in this population.

The literature describing respiratory manifestations in EDS and G-HSD has generally been limited to a few observational studies and case series involving mainly 4 subtypes: classical EDS, vascular EDS, hEDS, and G-HSD [2,9]. We chose to focus on the population with hEDS, as hEDS comprises the major subtype of EDS, and there is also a study highlighting respiratory muscle weakness and effectiveness of IMT [11]. The population with G-HSD was also chosen, as G-HSD is defined to be on the continuum of EDS and represents one of the most common diagnoses in our GEAR rehabilitation program, and the respiratory sequelae of G-HSD have not been well characterized [3]. Another important consideration factored into our selection of the EDS population was the risk of pneumothorax, which is generally lower in individuals with hEDS and G-HSD than in those with other subtypes. Thus, the inclusion of patients with hEDS and patients with G-HSD is owing to the representation of the majority (>90%) of the patients with EDS followed in our program.

We hypothesize that IMT and standard-of-care rehabilitation will provide a positive synergistic effect on respiratory muscle function, PROMs, and clinical outcomes. IMT has been shown to improve dyspnea by increasing respiratory muscle strength [76]. In addition, aerobic and strength training has been shown to increase the strength of the respiratory and limb muscles and improve oxygen use, ventilatory efficiency, and exercise capacity [20,31]. Furthermore, IMT can have positive effects on dyspnea through neurocognitive adaptations [77]. Breathing exercises may induce motor-sensory neural adaptations in the diaphragmatic and respiratory muscles, which can improve dyspnea tolerance [77]. It is also postulated that improvements in exercise capacity and dyspnea levels through IMT may result in greater independence in daily activities and improved HRQL [78]. Despite the proposed beneficial effects of IMT, the ideal duration remains to be determined, with 8 weeks chosen for this study based on the recommendation that a duration of at least 6 weeks is required to derive respiratory muscle adaptations [79-81].

Owing to the COVID-19 environment, a large proportion of research assessments and in-person care visits have transitioned to a web-based environment [82,83]. Patients often express concerns about the possibility of COVID-19 exposure and travel expenses for in-person assessments. Furthermore, the GEAR program has also adapted its format, with a proportion of web-based training sessions performed. Thus, we are closely monitoring enrollment numbers and if recruitment proves to be challenging because of the requirement for in-person visits, we will be able to amend the protocol to allow assessments to be performed via the web. In fact, most of the assessments in this study can be administered via the web, including all PROMs, respiratory muscle endurance testing, and IMT with electronic tracking on the device itself. The results of this study will demonstrate the potential of performing web-based IMT, especially with the emergence of tele-rehabilitation programs.

This study has several limitations that need to be highlighted. First, our study focuses on hEDS and G-HSD, which represent most EDS disorders in our program. However, the findings may not be generalizable across less prevalent EDS subtypes (eg, classic EDS or vascular EDS). Second, all participants in this RCT will be enrolled in the GEAR program, and we anticipate that any differences in training volumes or physical activity levels will be negligible between the groups after randomization, but any differences over the 8-week IMT program will be explored. Third, we are unable to monitor adherence to the GEAR program in the intervention group. Moreover, IMT may not be suitable for all participants because of time restrictions, training preferences, and work-school schedules. However, the web-based environment provides participants with the flexibility to uptake the IMT program that best suits their schedules.

This study aims to provide a better understanding of the contributors to dyspnea in hEDS or G-HSD and highlight the association between dyspnea and respiratory muscle function, PROMs, and exercise capacity. The combination of IMT and standard-of-care rehabilitation training may provide a novel therapeutic strategy to improve respiratory muscle function and PROMs. A better understanding of the feasibility and efficacy of IMT and standard-of-care rehabilitation will provide insight into the use of IMT in the population with EDS and the population with G-HSD, given a shift toward tele-rehabilitation programs in the COVID-19 environment. This research will pave the way for future studies to evaluate respiratory management strategies in this population.