Effectiveness of physical activity interventions on reducing perceived fatigue among adults with chronic conditions: a systematic review and meta-analysis of randomised controlled trials

Fatigue is barrier of physical activity participation in adults with chronic conditions. However, physical activity alleviates fatigue symptoms. This systematic review and meta-analysis aimed to (1) synthesise evidence from randomised controlled trials (RCTs) exploring the effects of physical activity interventions on fatigue reduction and (2) evaluate their effectiveness. Medline/CINAHL/EMBASE/Web of Science and Scopus were searched up to June 24th, 2023. Two reviewers independently conducted study screening and selection (RCTs), extracted data and assessed risk of bias (RoB2). Outcome was the standardised mean difference (SMD) with 95% confidence intervals in fatigue between experimental and control groups. 38 articles met the inclusion criteria. Overall, physical activity interventions moderately reduced fatigue (SMD = 0.54, p < 0.0001). Interventions lasting 2–6 weeks demonstrated a larger effect on fatigue reduction (SMD = 0.86, p < 0.00001). Interventions with 18–24 sessions showed a large effect on fatigue reduction (SMD = 0.97, p < 0.00001). Aerobic cycling and combination training interventions had a large to moderate effect (SMD = 0.66, p = 0.0005; SMD = 0.60, p = 0.0010, respectively). No long-term effects were found during follow-up. Physical activity interventions moderately reduced fatigue among adults with chronic conditions. Duration, total sessions, and mode of physical activity were identified as key factors in intervention effectiveness. Further research is needed to explore the impact of physical activity interventions on fatigue.

The prevalence of chronic conditions rises with age, with approximately 62% of Americans aged 65 and above having at least one chronic condition 1-3 .Fatigue is a common and complex symptom reported by individuals with various chronic conditions (e.g., cancer, Parkinson's Disease, inflammatory arthritis, and fibromyalgia) [4][5][6][7] .Despite its common occurrence, fatigue lacks a clear definition due to its multidimensionality, encompassing physical, mental, cognitive, emotional, and motivational fatigue [8][9][10] .Within the literature, fatigue is described as a disruptive, severe, and overwhelming symptom with cognitive elements among adults with chronic conditions 8,[11][12][13][14] .The prevalence of fatigue in this population ranges from 39 to 80% 6,[15][16][17][18] , making it a significant factor associated with limitations in functional independence and a barrier to engaging in physical activity (PA) for individuals with chronic conditions experiencing fatigue symptoms [19][20][21] .
Furthermore, fatigue often co-exists with other medical symptoms, such as pain, depression, and cognitive deficit 22 .Also, significant fatigue can have a detrimental effect on daily activities and health-related quality of life among individuals with chronic conditions 19,[23][24][25] .In daily life context, fatigue exhibits multiple negative effects, which have been observed to progressively escalate from impaired attention and reduced PA levels to increased risk of falls, disabling conditions, and mortality 9,26 .In general, fatigue has a negative impact on health and functioning of individuals with chronic conditions, leading to a decrease in their health-related quality of life 27 .Yet, the experience of fatigue symptoms often correlates with lower exercise engagement and a lack of independence 28,29 .
Lack of PA engagement is prevalent among adults with chronic conditions across the lifespan 19 .Fatigue can act as a barrier to activity engagement, as intense exercise during periods of fatigue can cause a negative affective load, further discouraging future engagement in activities 30,31 .However, the relationship between PA and fatigue is complex, with conflicting outcomes suggesting both positive effects of PA on fatigue reduction and the negative impact of fatigue on PA participation 9,20 .While some recommendations suggest that PA might reduce fatigue symptoms [32][33][34][35] , other studies indicate limited or no effects of exercise therapy on fatigue among adults with chronic fatigue syndrome 36 and Parkinson's disease 37 .Nevertheless, PA offers benefits for overall functioning, health, well-being, and quality of life and is associated with a reduced risk of premature mortality 13,[38][39][40][41][42] .Specifically, exercise and PA interventions in adults with mild cognitive impairments have shown positive effects on cognitive function 40,43 .Additionally, resistance training has also demonstrated favorable outcomes in measures Eligibility criteria.Randomised controlled trials of PA interventions for adults with chronic diseases with fatigue reported as a primary or secondary outcome were included.Eligible RCTs included adult participants who were assigned randomly to a physical intervention or a control group.In addition, articles should have reported primary research studies in English.Excluded were protocol papers, editorials, discussion papers, and comments.Moreover, tailored interventions for the participants were excluded since this review aims to explore specific intervention programs that are based on objective and specific criteria for the PA intervention.
Data management and screening.The EndNote software version 20.4 was used to remove the duplicates and the remaining results were imported to Rayyan 57 , which is a web tool designed for systematic reviews.Titles and abstracts were screened by two independent reviewers (IB and KES) to determine whether they met the eligibility criteria.The non-eligible abstracts were rejected, and numbers were documented.The full texts of potentially eligible studies were retrieved and assessed independently by IB and KES.All decisions of inclusion or exclusion were automatically recorded in Rayyan, and reviewers were blinded to each other's decisions.Any disagreements were discussed and resolved by consensus between the two reviewers or by consulting a third reviewer (FJH).The outcome data that were used for the meta-analysis were extracted by IB.Uncertainties about outcome data were discussed with KES and USA and the original paper was accessed to reach an agreement.

Statistical analysis.
The primary outcomes in the meta-analysis included the effect of different PA interventions on perceived fatigue as a first step.Then, the effects of the length and total sessions of interventions and the mode of PA on perceived fatigue were investigated as a second step in which we aimed to explore different ingredients of the interventions.In the analyses, the studies were distributed in different subgroups based on: • the length of the interventions (2-6 weeks, 7-10 weeks, 11-15 weeks, 16 + weeks) • the total sessions of the interventions (8-16 sessions, 18-24 sessions, 30-36 sessions, 45-48 sessions, 54 + ses- sions) • the mode of PA (aerobic running, aerobic cycling, balance, resistance, combination, exergaming aerobic, horseback riding) In addition, meta-analysis was conducted for the studies that included the post-trial follow ups, which assesses the effect retained at follow up, thus indicating the long-term effects.Random effects models were used for the inverse variance meta-analysis conducted in the Review Manager software (Review Manager 5.4; The Nordic Cochrane Centre, The Cochrane Collaboration).Because the interventions used different scales for the fatigue assessment, we performed standardised mean differences (SMD).SMD with 95% confidence intervals (CI) was used to describe the experimental and control group differences for post-intervention values in PA intervention subgroups as well as the overall effect.In addition, post-trial follow-ups were considered if appropriate.SMD values of 0.2, 0.5, and 0.8 represent a low effect, a moderate effect, and a large effect, respectively 59 .When the potentially eligible articles did not report mean (M) and standard deviation (SD), the corresponding authors were contacted by email to request the data.The articles were excluded from the meta-analysis if there was no reply within two weeks; however, they were included in the systematic review.
Statistical heterogeneity among studies was assessed by calculating the I 2 index.Low heterogeneity was considered when I 2 ≤ 25%, moderate when I 2 ≤ 50% and > 25%, and high when ≤ 75% and > 50% 60 .Subgroup analysis was used to analyse the effectiveness of the PA interventions.
Moreover, among 31 studies, included in our analysis, five studies consisted of two experimental groups and one control group [61][62][63][64][65] .To ensure consistency, we examined whether the groups within each study belonged to the same PA mode.If both groups shared the same PA mode as well as intervention length, and total sessions, they were combined for the meta-analysis.Conversely, if different PA modes were used within the same study experimental groups, they were analysed separately.
The fatigue severity scale (FSS) was used in twenty-three studies and was the most frequently used fatigue measure among the thirty-eight studies.The FSS is a validated and reliable 9-item questionnaire designed to assess the impact of perceived fatigue among adults diagnosed with chronic conditions [100][101][102] .The functional assessment of chronic illness therapy-fatigue scale (FACIT-F) was used in seven studies.FACIT-F (version 4) is a 40-item questionnaire evaluating self-reported fatigue and its influence on everyday activities and function among adults with cancer and older people who experience fatigue 103 .It is valid and reliable in several patients' populations [104][105][106] .One study used the fatigue assessment questionnaire (FAQ), which is a validated 20-item questionnaire assessing fatigue among adults with cancer 107,108 .The modified fatigue impact scale (MFIS) was used by one study and contains 9 items 109 .MFIS provides an assessment of the effects of fatigue in physical and cognitive functioning and is reliable and valid in several clinical populations 110 .The multidimensional fatigue inventory (MFI) is 20-item questionnaire evaluating fatigue and was used by one study 111 .MFI is valid and reliable in several chronic conditions 112,113 .The visual analogue scale (VAS) is an 18-item questionnaire evaluating

Risk of bias.
The Cochrane tool was used to assess the risk of bias in included studies (n = 38).Figure 2a and b show the risk of bias analysis.Overall, twenty-five studies showed a high risk of bias, and thirteen studies showed some concerns.The trials by Etnier et al. 92 , Rios Romenets et al. 94 and Van Den Berg et al. 75 presented a high risk of bias in the domain of randomization process.Whereas 18 trials showed a low risk of bias in this The trials conducted by Duruturk et al. 65 , Ozkul et al. 72 and Petajan et al. 73 showed high risk of bias in the deviations from intended intervention.While only three trials presented as low risk 77,83,98 .In the domain of missing outcome data, 22 trials presented a low risk of bias 37, 61, 68, 70, 72, 74, 76, 79-81, 83-86, 90, 91, 93, 95-99 while only four presented a high risk of bias 62,64,78,88 .15 trials showed a low risk of bias 61, 70-72, 78, 79, 83, 86, 87, 90, 91, 93, 95-97 in the measurement of outcome domain while three showed a high risk of bias 73,74,88 .

Effects of PA interventions on perceived fatigue.
Initially, a meta-analysis was conducted to investigate the effects of all the included PA interventions on perceived fatigue.Eventually, 31 articles out of the 38 were included in the meta-analysis.The test for overall effect indicates that there is a moderate effect for reduction in perceived fatigue based on random effects model (SMD = 0.54; 95% CI = 0.79 to 0.29; p < 0.00001) with high heterogeneity results between studies (I 2 = 79%).The outcomes are illustrated in Fig. 3.The effects of the intervention length on perceived fatigue are presented in Fig. 4. The test for subgroup differences was not statistically significant with low heterogeneity (p = 0.38, I 2 = 2.5%).Interventions that lasted for 2-6 weeks have a larger effect (SMD = 0.86; 95% CI = 1.24 to 0.48; p < 0.00001) compared to interventions that were 7-10 weeks (SMD = 0.76; 95% CI = 1.22 to 0.29; p = 0.001).The results from the interventions that were 2-6 weeks showed low heterogeneity (I 2 = 10%) while the results from the interventions that were 7-10 weeks showed high heterogeneity (I 2 = 79%).Moreover, the interventions that were 11-15 weeks showed a low effect for perceived fatigue (SMD = 0.48; 95% CI = 0.76-0.20;p = 0.0008) and results were heterogeneous between studies (I 2 = 72%).No effect was found for the interventions that were 16 weeks + (SMD = 0.07; 95% CI = 1.86-1.73;p = 0.94) and results were heterogeneous between studies (I 2 = 93%).
The effects of the mode of PA interventions on perceived fatigue are illustrated in Fig. 6.Overall, the test for subgroup differences suggests that there is a statistically significant subgroup effect based on a random model with high heterogeneity (p = 0.002; I 2 = 71.2%).Meta-analysis showed no effect for perceived fatigue in the aerobic running training subgroup (SMD = 1.25; 95% CI = − 3.61 to 1.11; p = 0.30) and results between studies were heterogenous (I 2 = 89%).The estimates showed a moderate effect for perceived fatigue in the aerobic cycling

Discussion
In this meta-analysis, data from 33 randomised control trials were synthesized to examine the effectiveness of PA interventions in reducing perceived fatigue among adults with chronic conditions.To the best of our knowledge, this is the first study to comprehensively evaluate the impact of PA interventions on perceived fatigue across a range of chronic conditions.
Firstly, this meta-analysis demonstrates that PA interventions have a moderate effect on perceived fatigue (SMD = 0.54) among adults with chronic conditions.Previous studies investigating the effects of PA on fatigue have yielded inconsistent findings.Some studies have demonstrated a positive association between exercise and fatigue in adults with chronic conditions 118,119 .Others, have reported that PA can reduce both fatigue and pain 33,35,120 , while contradictory results have indicated no effect of exercise on fatigue 37,121 .Our meta-analysis identifies a moderate effect of PA on fatigue reduction, providing new insights for the future design of targeted PA interventions to alleviate fatigue in individuals with various chronic conditions 121,122 .
Regarding the intervention length, this meta-analysis revealed that trials lasting from two to ten weeks 2-10 demonstrated a large to moderate effect on perceived fatigue among adults with chronic conditions (SMD = 0.86, 0.76, respectively).Additionally, the subgroup of eleven to fifteen showed a low to moderate effect (SMD = 0.48) However, high heterogeneity was observed in the seven to ten weeks and eleven to fifteen weeks subgroups, potentially influenced by other intervention characteristics such as total sessions or mode of PA or even the disease diagnosis.In contrast, low heterogeneity was found in the 2-6 weeks intervention length, although the limited number of trials in this subgroup may be a limitation.Trials lasting from sixteen to 24 weeks were found to have no effect on perceived fatigue, with high heterogeneity and limited trials in this subgroup posing potential limitations.Additionally, adherence to the intervention was reported in two out of the four trials in this subgroup 71,80,81,92 , with adherence rates of 65% 92 and 93.3% 71 .Due to lack of adherence reporting, we cannot definitively conclude that adherence might be a reason for the low effect on perceived fatigue.The duration of an intervention holds importance for health professionals and researchers, as clinical and health interventions often face budget constraints 122 .While this meta-analysis suggests a trend of shorter PA interventions being effective for alleviating fatigue, other factors may influence the results.Therefore, future research is necessary to determine the optimal and effective intervention duration, considering factors such as cost-effectiveness and time-efficiency in research and rehabilitation settings.The exploration of total sessions in PA interventions yielded interesting findings.It was observed that interventions comprising 18-24 sessions had a substantial impact on perceived fatigue (SMD = 0.97).The considerable heterogeneity observed in the results could be partially attributed to other intervention characteristics, such as intervention duration and mode.On the other hand, subgroups with 8-16, 30-36, 45-48, and 54+ total sessions showed no effect on perceived fatigue.The uneven distribution of studies among these subgroups might have limited the analysis of their effects on the total sessions of the interventions.Thus, researchers should be careful when interpreting the pooled effect sizes and focus on the observed data patterns.Furthermore, the duration of PA sessions and adherence to weekly PA also play crucial roles in achieving desirable outcomes.However, investigating this element in the meta-analysis proved challenging due to the inclusion of various chronic conditions, each with their specific PA guidelines, although they share some similarities.
Moreover, this meta-analysis revealed that aerobic cycling and combination training have moderate effects on perceived fatigue in adults with chronic conditions (SMD = 0.66, and 0.60, respectively).However, there was variation in heterogeneity among these subgroups.The aerobic cycling training subgroup exhibited no heterogeneity.However, it is important to note that this subgroup had a limited number of studies, which could have influenced the results.In contrast, the combination training subgroup, incorporating different training components such as aerobic, resistance, and balance exercises, displayed high heterogeneity across the studies.The heterogeneity could be attributed by the variations in the combination training programs implemented.Existing literature suggests that aerobic and resistance training have been effective in alleviating fatigue symptoms among individuals with chronic conditions 33,[123][124][125] .Conversely, treadmill running has shown no improvement in fatigue symptoms 119 .Therefore, the literature provides conflicting findings regarding the effects of different PA modes on fatigue, necessitating further exploratory studies in this area.Furthermore, the importance of PA enjoyment has been highlighted in the literature, as it has been observed that individuals who find an activity enjoyable are more likely to stay engaged and experience PA benefits while reducing their fatigue symptoms 50 .Additionally, individuals with chronic disorders may experience discomfort and other symptoms such as shortness of breath during aerobic training; underscoring the need for personalised options tailored to their specific needs.The inclusion of a range of PA modes seems promising, as it allows for choice, but further research is needed in this regard.
The effects of PA interventions on fatigue reduction on post-trial follow up were examined in eight studies included in this review, which revealed no significant effect of the PA intervention on fatigue reduction during the follow up.However, it is important to note that the level of PA participation between the end of the intervention and the follow up period was not clearly outlined in the included studies.Among the two studies that reported guidance during follow up, conflicting approaches were observed.One study motivated participants to maintain an active lifestyle and continue exercising, while another study encouraged them to resume their pre-intervention daily routine to assess the effects of the intervention after a period of inactivity.The contrasting guidance provided to participants could have influenced the effects of PA interventions on fatigue during follow up, as sustained PA during this period might suggest that the effects on fatigue could be diminished in the long term.Furthermore, the scarcity of studies and the high heterogeneity preclude definitive conclusions regarding the sustained effect of PA interventions on fatigue reduction.Nevertheless, it was observed that most PA interventions do not include post-trial follow up measurements, which are essential for identifying potential risks that may not be evident during the trial period 126,127 .In many cases, after the standardised intervention length, adults with chronic conditions struggle to remain physically active.Notably, a study aiming to promote long term PA adherence after rehabilitation discharge in individuals with chronic conditions demonstrated successful outcomes even one year after follow-up 128,129 .
Individuals with chronic conditions often experience fatigue, leading to activity avoidance or underactivity 24 .Therefore, it is important to distribute activities throughout the day more effectively 24 .Interestingly, none of the included interventions considered incorporating self-regulatory strategies such as activity pacing (regulation of activity levels) to participants 130 .Integrating activity pacing guidance, taught by healthcare professionals (e.g., occupational or physical therapists) can foster a balanced and active lifestyle, effectively managing fatigue symptoms and promoting physical activity engagement 4,24,[131][132][133] .Moreover, self-regulatory skills have been found important for moderate to vigorous intensity PA and relevant for addressing fatigue complaints 132,134,135 .Thus, self-regulation should be considered in PA interventions, particularly when aiming for sustained physical activity engagement, facilitating the adaption of individuals with fatigue to the new PA lifestyle changes.Overall, the combination of activity pacing and self-regulation holds promise in achieving a physically active lifestyle while effectively managing in the long term 135 .Therefore, it is imperative to explore long term strategies and implement follow up measures that aim to reduce fatigue symptoms among adults with chronic conditions while maintaining PA engagement over time.
Furthermore, our transdiagnostic approach focusing specifically on fatigue symptoms, emphasizes the significance of addressing fatigue symptoms through PA, which can yield numerous benefits.Wilson and Cleary's health-related quality of life model, highlights the interconnectedness of symptom status, which influences functional health, which influences the general health perception, which consequently influences the overall quality of life 136 .Applying this model to our findings may suggest that improving quality of life in individuals with chronic conditions can be achieved by reducing fatigue symptoms through PA 51 .This perspective could indicate the potential of PA to positively impact the overall well-being and functioning of individuals with chronic conditions.Further research is recommended to provide further evidence on this approach.
Strengths and limitations.This review possesses several key strengths.It is the first systematic review/ meta-analysis to follow a transdiagnostic approach on this specific topic.This approach might enhance the generalizability of the findings and provide important insights into the effects of PA interventions on fatigue reduction across multiple chronic conditions.Additionally, this review synthesises data from thirty-three interventions, allowing for a comprehensive evaluation of the effects and providing a robust foundation for recommendations.
There are also some limitations of this review.Heterogeneity among the studies may limit the generalizability of our findings.Variations in the effects of PA interventions on fatigue may be attributed, in part, to intervention characteristics such as duration, sessions, and mode of PA.Furthermore, fatigue can vary across conditions with different severity levels 137 .Additionally, in the current review, over 65% of the studies were judged as high-risk based on the ROB2 assessment, primarily due to deviations from the intended interventions.Additionally, other elements of PA interventions posed challenges for inclusion in the meta-analysis.For instance, studies reported intensities differently or did not report them at all.Furthermore, the proportion of female participants was higher across the studies compared to males, which could have influenced the results given the higher prevalence of fatigue in females [138][139][140][141][142][143] .
Implications.In a transdiagnostic sample, this meta-analysis indicates that PA interventions have a moderate overall effect in reducing perceived fatigue among adults with chronic conditions.This finding indicates the potential integration of PA into fatigue management programs.However, the limited inclusion of follow up measures and long term effects emphasizes the need for further exploration of the sustained impact of PA on fatigue reduction.Additionally, the incorporation of activity pacing and self-regulation into long term interventions is crucial as these strategies have been identified as key factors in PA and fatigue management among adults with chronic conditions.Furthermore, it is important to critically assess and investigate the effectiveness of different ingredients of PA interventions while considering confounding factors, as these outcomes might have significant implications for both healthcare professionals and patients.

Conclusion
Fatigue poses a significant barrier to PA engagement among adults with chronic conditions but our findings provide robust evidence supporting the moderate effects of PA in reducing fatigue in this population.Our metaanalysis revealed that both aerobic cycling and combination training interventions demonstrated moderate effects on fatigue reduction.Furthermore, interventions lasting 2-10 weeks showed promising results in reducing fatigue in chronic conditions.However, the observed effects on fatigue during post-trial follow-ups were low, due to the lack of studies conducting follow up measurements underscoring the importance of further investigation into the long term effects of PA interventions.Additionally, further research is needed on the effects of the specific intervention ingredients as these findings hold valuable implications for health professionals and patients.

Figure 1 .
Figure 1.Flow diagram of trial selection, adapted from PRISMA.

Figure 2 .
Figure 2. (a) Risk of bias graph.(b) Risk of bias summary.

Figure 3 .
Figure 3. Forest plot of effects of physical activity interventions on perceived fatigue.

Figure 5 .
Figure 5. Forest plot of effects of total sessions of physical activity interventions on perceived fatigue.

Figure 6 .
Figure 6.Forest plot of effects of modes of physical activity interventions on perceived fatigue.

Table 1 .
2earch strategy for all databases including Boolean operators for each domain.MeSH, Medical Subject headings.*Usedtoidentifyall words beginning with the stem.1Restrictedsearch to title, abstract and keywords.2Limitto English results.Fatigue assessment 1,2 (facit-f) OR (functional assessment of chronic illness therapy fatigue scale) OR (fatigue severity scale*) OR (fatigue assessment scale*) OR (fatigue assessment) OR (chalder fatigue scale) OR (chalder fatigue questionnaire) OR (chalder fatigue*) Target population 1,2