Abstract
This study suggests that interventions geared to improve peripheral factors of performance fatigability during exercise in interstitial lung disease may prove valuable to decrease patients’ perceived fatigability, since both seem closely related https://bit.ly/3lpIUPs
To the Editor:
A sizeable fraction (∼70%) of patients with fibrotic interstitial lung disease (f-ILD) suffer from and seek medical advice due to debilitating symptoms of fatigue [1]. Broadly, fatigue can be defined as an unrelenting feeling of tiredness or lack of energy that is not improved by rest. However, fatigue is a complex symptom, thus remains poorly understood and not appropriately treated in f-ILD [2].
Fatigue is thought to originate from predisposing, precipitating and perpetuating factors that are not necessarily specific to f-ILD, although most factors may be applicable to the disease (as reviewed in [2]). In this letter, we reason using the renowned framework for fatigue offered by Enoka and Duchateau [3] in which “perceived” and “performance” fatigability interact to limit one's physical (and cognitive) functioning.
Perceived fatigability refers to an individual's sensations about fatigue [4]. Of note, it can be assessed as a trait characteristic (i.e. the amount of fatigue faced by patients over a prolonged period of time) or as a state level (i.e. the amount of fatigue faced at a specific moment in time, such as physical tasks) [4]. Performance fatigability corresponds to the objective changes in performance relative to the requirements brought by a specific task. This component depends on the ability of the neuromuscular system to meet such specific requirements and may be divided into central (e.g. voluntary activation) and peripheral (e.g. tissue oxygen (O2) delivery) factors [4].
However, it is unknown whether sensations of fatigue relate, at least in part, to alterations in neuromuscular mechanisms in patients with severe f-ILD. In this context, we aimed to offer a comprehensive assessment of fatigue in patients with f-ILD comprising both perceived (trait/state level) and performance fatigability and assess relationships between these two components.
16 patients (13 men; mean±sd age 73±8 years; 10 with idiopathic pulmonary fibrosis; mean±sd total lung capacity 63±15% predicted, mean±sd transfer factor of the lung for carbon monoxide 42±10% pred) were recruited from the ILD clinic (Division of Respirology, Queen's University and Hotel Dieu Hospital, Kingston, ON, Canada) between November 2018 and February 2020. They first performed an incremental (typically 5–15 W increment every 2 min [5, 6]) exercise test on a bicycle ergometer to determine peak work rate (WRpeak). All patients had severe exertional hypoxaemia (room air nadir of O2 saturation by pulse oximetry <88% [7]). On a different day, they performed a constant-load bicycle exercise test (60% WRpeak) to symptom limitation [8]. Magnetic femoral nerve stimulation assessed quadriceps neuromuscular fatigability [8]. Peripheral and central components of performance fatigability were measured as the pre- to post-exercise reduction in the potentiated quadriceps twitch amplitude (ΔTw) and voluntary activation (ΔVA, interpolated twitch technique [9]), respectively [10]. ΔTw and ΔVA were also expressed as a function of the external work (kJ) (work rate (W)×exercise time (s)/1000) performed during constant-load exercise test. The state level of perceived fatigability was assessed using the Rating-of-Fatigue (ROF) scale, a valid tool to measure the intensity of fatigue in various contexts, such as whole-body exercise [11]. Perceived fatigability as a trait was assessed with the Fatigue Severity Scale (FSS) [12], a tool validated in a large sample to assess and quantify this outcome for clinical and research purposes [13] and used previously in f-ILD [14]. Patients were then discriminated according to their FSS (trait) and ROF (state) scores as “less fatigued” or “more fatigued”, using a cut-off of 38 points (FSS) and 0.14 units·kJ−1 (ROF). These cut-off scores corresponded to the median sample score for each scale. This prospective study was approved by the Queen's University (Kingston, Canada) research ethics board (DMED-2150-18). Written informed consent was obtained from each participant prior to their participation.
Moderate and severe perceived fatigability as a trait (FSS) were reported by 12 (75%) out of 16 and six (38%) out of 16 patients with f-ILD, respectively [15]; specifically, less fatigued patients had mean±sd FSS scores of 29±10 and more fatigued patients had a score of 48±5 (p<0.001). On average, patients exercised at 43±13 W for 17.0±4.0 min, leading to 44.4±19.0 kJ of work (with no difference according to FSS subgroups). Indices of performance fatigability (Δ maximal voluntary contraction (MVC), ΔTw and ΔVA, both absolute and work-corrected values) did not differ between FSS subgroups, nor did they correlate with FFS scores (p>0.05). Similarly, perceived fatigability as a state (i.e. on exercise: ROF scores, both absolute and work-corrected) did not differ between less versus more fatigued patients: 6.3±2.1 versus 6.0±1.7 ROF units, and 0.20±0.12 versus 0.14±0.06 ROF units·kJ−1 at exercise cessation, respectively (both p>0.05); there was no correlation between trait and state levels of perceived fatigability (p>0.05).
Considering perceived fatigability as a state, less fatigued and more fatigued patients had ROF scores of 5.6±1.9 versus 6.6±1.8 ROF units (p>0.05) and 0.10±0.03 versus 0.24±0.08 ROF units·kJ−1 (p=0.001) at exercise cessation, respectively. This was due to less external work performed in more fatigued patients: 29.7±12.1 versus 59.0±11.6 kJ (p<0.001). When ROF scores were work-adjusted, ΔTw did not differ between less and more fatigued patients: −21.3±10.2% versus −20.9±7.6% drop from baseline, respectively (p>0.05). However, ΔTw/work was larger in more fatigued patients: −0.72±0.13%·kJ−1 versus −0.38±0.20%·kJ−1 (p=0.001) (figure 1a). In fact, ROF and ΔTw strongly correlated (r= −0.80; p<0.001) when adjusted for external work (figure 1b). Other indices of performance fatigability (ΔMVC and ΔVA, both absolute and work-corrected) neither differed between ROF subgroups nor correlated with ROF scores (p>0.05) (figure 1c,d).
Fatigue assessment in f-ILD has so far been restricted to a trait characteristic [2]. The present study is innovative because it offers a thorough assessment of fatigue, comprising both components of perceived (trait and state levels) fatigability and directly measured performance fatigability. We found that 1) trait level of perceived fatigability was not linked to performance fatigability, but, in contrast, 2) state level of perceived fatigability and performance fatigability elicited by exercise correlated significantly when corrected for external work performed in f-ILD. Our approach seems particularly relevant when considering the multidimensional facets of a complex symptom, which can hardly be captured by a single measure.
Paneroni et al. [16] recently found a similar mismatch between trait level of perceived fatigability and performance fatigability on exercise in severe to end-stage COPD. They reported that FSS was inversely related to forced expiratory volume in 1 s, that is, perceived fatigability was associated with the severity of airflow obstruction. Applying such reasoning, we found that FSS inversely correlated with forced vital capacity (r= −0.52; p=0.038), suggesting that greater perceived fatigability was associated with the severity of lung restriction in our sample. However, perceived fatigability did not correlate with other relevant variables such as exercise tolerance (peak O2 uptake or work rate) or the extent of exertional hypoxaemia (p>0.05). Owing to the fact that fatigue in f-ILD is multifactorial, its management may require a comprehensive approach, comprising, for instance, optimised treatment of the underlying disease and other associated comorbidities (e.g. sleep apnoea or obesity) or supportive measures (e.g. cognitive behavioural therapy) [2].
Importantly, perceived fatigability and the peripheral component of performance fatigability during exercise were strongly associated in f-ILD. In this context, acute and chronic interventions aiming at lessening peripheral impairments underlying fatigability might translate into beneficial effects on perceived fatigability during physical exertion in this population. Specifically, in such patients with severe exercise-related hypoxaemia, acute strategies targeting enhancement of muscle O2 delivery (e.g. supplemental O2 [8] or nitrate intake [17]) may be of strong interest. From a chronic standpoint, rehabilitative exercise training producing favourable changes in muscle structure and function has been related to improved muscle fatigability in other respiratory disorders [18]. The corollary is that lessening exercise-related fatigability may help patients being more active [14], physical inactivity being itself a perpetuating factor for fatigue in f-ILD [2]. Of note, we only enrolled a small sample of patients with severe f-ILD (mostly idiopathic pulmonary fibrosis). It is unknown whether similar results would be observed in milder forms or other aetiologies of f-ILD.
In conclusion, we found no association between trait level of perceived fatigability and performance fatigability in patients with severe f-ILD. Conversely, state level of perceived fatigability and the peripheral component of performance fatigability for a given amount of work were strongly associated in this patient population. Interventions improving peripheral factors associated with performance fatigability during physical exertion (e.g. O2 supplementation or exercise training) may prove valuable to decrease patients’ symptoms, such as heightened perceived fatigability.
Acknowledgements
The authors thank Angie Zapotichny, Filipa Saramago and Brandon Palmer (Kingston Health Sciences Centre, Kingston, ON, Canada) and the different members of the Respiratory Investigation Unit (Queen's University, Kingston) for their continuous assistance.
Footnotes
Provenance: Submitted article, peer reviewed.
This ancillary study is a part of a larger project aiming at investigating the physiological effect of oxygen supplementation on peripheral muscle fatigability in fibrotic interstitial lung disease. The authors thus want to disclose that these data (i.e. peripheral muscle fatigability) have been published elsewhere [8]. However, other data and the rationale/analyses herein presented are original and unpublished.
Author contributions: M. Marillier and A-C. Bernard collected the data. M. Marillier analysed the data. M. Marillier, M. Gruet, A-C. Barnard, S. Verges, O. Moran-Mendoza and J.A. Neder were involved in the interpretation of the results. M. Marillier, M. Gruet and J.A. Neder drafted the first version of the manuscript and all authors provided critical feedback to shape the final version of the manuscript. All authors approved the final version of the manuscript to be published and agree to be accountable for all aspects of the present work.
Conflict of interest: M. Marillier was a recipient of a Long-Term Research Fellowship (LTRF 2018) from the European Respiratory Society to support his post-doctoral stay at Queen's University. J.A. Neder is an associate editor of this journal. The remaining authors have nothing to disclose.
Support statement: This study was supported by European Respiratory Society grant LTRF 2018 to M. Marillier. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received December 21, 2022.
- Accepted February 6, 2023.
- Copyright ©The authors 2023
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