ANNALES KINESIOLOGIAE • 14 • 2023 • 2 143 Review article DOI: https://doi.org/10.35469/ak.2023.425 received: 2023-12-07 UDC: 796.015:616.891.4 EFFECTS OF GRADED EXERCISE THERAPY AND MEDICAL CARE ON CHRONIC FATIGUE SYNDROME Tamara ZLIČIĆ 1 , Darinka KOROVLJEV 1 , Tijana ŠĆEPANOVIĆ 1 , Ivana MILOV ANOVIĆ 1 1 Faculty of Sport and Physical Education, University of Novi Sad, Serbia Corresponding author: Tamara ZLIČIĆ Faculty of Sport and Physical Education, University of Novi Sad, Serbia, Lovćenska 16, 2100 Novi Sad, Serbia, Phone: +381 21 450 188 E-mail: tamara.zlicic@uns.ac.rs ABSTRACT Purpose: Chronic Fatigue Syndrome (CFS) / Myalgic Encephalomyelitis (ME) is a complex condition with debilitating symptoms that significantly impact individuals, particularly those in the working population. This study aims to investigate the effec- tiveness of Graded Exercise Therapy (GET) and Cognitive Behavioral Therapy (CBT) along with additional methods such as Graded Exercise Self-help (GES), Adaptive Pac- ing Therapy (APT), and Specialist Medical Care (SMC), in managing Chronic Fatigue Syndrome (CFS) / Myalgic Encephalomyelitis (ME) among the working population. Methods: A systematic analysis of five randomized controlled trials conducted be- tween 2013 and 2023, encompassing GET, CBT, APT, SMC, and GES was performed using PubMed. Results: The selected studies consistently demonstrate that GET positively impacts physical functioning and reduces fatigue levels in working individuals with CFS. Ad- ditionally, CBT proves valuable, emphasizing the importance of addressing the mental aspects of CFS in occupational contexts. Conclusion: This review underscores the need for further research, advocating for direct assessment methods like biomarkers to enhance our understanding of CFS and improve treatment outcomes. These insights are crucial for healthcare practitioners, researchers, and policymakers navigating the complexities of CFS within the work- place. Emphasizing the integration of psychological interventions with physical thera- 144 Tamara ZLIČIĆ, Darinka KOROVLJEV , Tijana ŠĆEPANOVIĆ, Ivana MILOV ANOVIĆ: EFFECTS OF GRADED EXERCISE THERAPY ... , 143–154 ANNALES KINESIOLOGIAE • 14 • 2023 • 2 pies is essential for a comprehensive approach to managing CFS among the working population. Keywords: Chronic Fatigue Syndrome / Myalgic Encephalomyelitis, CFS/ME, graded exercise therapy, cognitive behavioral therapy, adaptive pacing therapy, spe- cialist medical care, working population. UČINKI STOPNJEV ANE V ADBENE TERAPIJE IN ZDRA VSTVENE OSKRBE NA SINDROM KRONIČNE UTRUJENOSTI IZVLEČEK Namen: Sindrom kronične utrujenosti (CFS)/mialgični encefalomielitis (ME) je za- pletena bolezen z izčrpavajočimi simptomi, ki močno vplivajo na posameznike, zlasti na delovno aktivno prebivalstvo. Namen te študije je raziskati učinkovitost stopnjeva- ne vadbene terapije (GET) in kognitivno-vedenjske terapije (CBT) skupaj z dodatnimi metodami, kot so stopnjevana vadba za samopomoč (GES), terapija s prilagojenim tempom (APT) in specialistična zdravstvena oskrba (SMC), pri obvladovanju sindroma kronične utrujenosti (CFS)/mialgičnega encefalomielitisa (ME) med delovno popula- cijo. Metode: Sistematična analiza petih randomiziranih nadzorovanih raziskav, opravlje- nih med letoma 2013 in 2023, ki vključujejo GET, CBT, APT, SMC in GES, je bila opra - vljena s pomočjo PubMeda. Rezultati: Izbrane študije dosledno dokazujejo, da GET pozitivno vpliva na telesno delovanje in zmanjšuje stopnjo utrujenosti pri zaposlenih posameznikih s CFS. Poleg tega se CBT izkaže za koristno, kar poudarja pomen obravnave duševnih vidikov CFS v poklicnem kontekstu. Sklep: V pregledu je poudarjena potreba po nadaljnjih raziskavah, pri čemer se zagovarja neposredne metode ocenjevanja, kot so biomarkerji, da bi izboljšali naše razumevanje CFS in izboljšali rezultate zdravljenja. Ta spoznanja so ključna za zdra- vstvene delavce, raziskovalce in oblikovalce politik, ki se spopadajo z zapletenostjo CFS na delovnem mestu. Poudarjanje vključevanja psiholoških intervencij v vadbene terapije je bistvenega pomena za celovit pristop k obvladovanju CFS med delovno ak- tivnim prebivalstvom. Ključne besede: sindrom kronične utrujenosti/mialgični encefalomielitis, CFS/ME, stopnjevana vadbena terapija, kognitivno-vedenjska terapija, terapija s prilagojenim tempom, specialistična zdravstvena oskrba, delovna populacija. ANNALES KINESIOLOGIAE • 14 • 2023 • 2 145 Tamara ZLIČIĆ, Darinka KOROVLJEV , Tijana ŠĆEPANOVIĆ, Ivana MILOV ANOVIĆ: EFFECTS OF GRADED EXERCISE THERAPY ... , 143–154 INTRODUCTION Chronic Fatigue Syndrome (CFS) / Myalgic Encephalomyelitis (ME) is a medical condition characterized by profound fatigue and a range of associ- ated symptoms, such as musculoskeletal pain, sleep disorders, cognitive im- pairments including concentration and memory deficits, headaches and a low tolerance for physical activity affecting individuals for six months or more (Prins, van der Meer, & Bleijenberg, 2006). Despite its significant impact, ef- fective medical responses are hindered by the lack of standardized diagnostic tests and a comprehensive understanding of its pathophysiology (Sandler & Lloyd, 2020). The etiology of CFS remains elusive, encompassing various theories related to viral infections, immune imbalances, hormonal factors, genetic predispositions, and psychological stress (Sandler & Lloyd, 2020). Recent epidemiological studies have highlighted a high prevalence of CFS, particularly among adults (Johnston, Brenu, Staines, & Marshall-Gradisnik, 2013) and predominantly affecting women (Faro et al., 2016). While there is no universal tool for assessing CFS patients comprehensively (Bergner et al., 1976), specific questionnaires, such as the Chalder Fatigue Question- naire (CFQ), are frequently used to assess the severity of symptomatic fa - tigue (Chalder et al., 1993), which has been shown to reliably discriminate between clinical and nonclinical conditions (Cella & Chalder, 2010), and the Multidimensional Fatigue Inventory (MFI-20) for comprehensive fatigue assessment (Shahid, Wilkinson, Marcu, & Shapiro, 2012). Additionally, vari- ous interventions have been proposed for managing CFS symptoms, includ- ing Cognitive Behavioral Therapy – CBT, Graded Exercise Therapy – GET, Adaptive Pacing Therapy – APT, Specialist Medical Care – SMC, and Grad- ed Exercise Self-help – GES. CBT addresses the cognitive, behavioral, and symptomatic aspects of CFS, guiding participants to develop coping strate- gies (White, Goldsmith, Johnson, Chalder, & Sharpe, 2013). GET gradually increases physical activity to improve fitness in CFS/ME treatment (Sharpe et al., 2015). APT manages energy through activity assessment and pacing (Walwyn et al., 2013), while SMC offers explanations, guidance, and medical recommendations (Clark et al., 2017) and GES involves a six-step exercise program (Clark et al., 2017). Given the significant impact of CFS/ME on the working population (Valdez et al., 2019), there is a critical need to analyze existing research and interventions specifically designed for this condition. Therefore, the aim of this article is to provide a concise yet comprehensive examination of the current research and interventions aimed at managing CFS/ME symptoms within the working population, highlighting the impor- 146 Tamara ZLIČIĆ, Darinka KOROVLJEV , Tijana ŠĆEPANOVIĆ, Ivana MILOV ANOVIĆ: EFFECTS OF GRADED EXERCISE THERAPY ... , 143–154 ANNALES KINESIOLOGIAE • 14 • 2023 • 2 tance of addressing the unique challenges faced by working individuals with this condition. METHODS The research methodology is based on a descriptive approach, involving the analysis of previous studies conducted between 2013 and 2023 using the PubMed domain using the words “CFS” OR “GET” OR “CBT” “APT” OR “SMC” OR “working population”. The search specifically focused on rand- omized controlled trials and the literature review concentrated on studies incor- porating the working population as a subject due to their increased vulnerability to this condition. The inclusion criteria were that participants involved in the study must have a diagnosed with CFS, belong to the working population, and the intervention in the treatment or prevention of CFS consisted of GET, CBT, APT, SMC, or GES. Additionally, the articles had to be written in the English language and the full text must be accessible. The exclusion criteria comprised studies addressing other forms of fatigue, those that did not specifically apply to research on the influence of physical activity on CFS, studies involving ado- lescents, and those assessing physical fitness after the administration of specific supplementation or medication. RESULTS The following results were obtained through the research of the PubMed database, based on keyword search and their combination, adhering to the in- clusive and exclusive criteria. A total of 61 articles were identified through data research, from which 19 abstracts were reviewed. All the identified arti- cles were read in full to assess eligibility and quality. In the end, a total of five articles were included in the review. An overview of the search and selection methodology procedure is described in Figure 1 through a Prisma diagram. Based on the results presented in Table 1 regarding the use of different pro- grams in the treatment of CFS, the outcomes for patients receiving GET or GES treatment combined with CBT indicated a reduction in fatigue, with patients re- porting an improvement in physical and cognitive functioning. SMC and APT showed improved outcomes in long-term follow-ups. In the study conducted by White et al. (2013), commonly known as the PACE study (Table 1), the effectiveness of different treatments for CFS in achieving ANNALES KINESIOLOGIAE • 14 • 2023 • 2 147 Tamara ZLIČIĆ, Darinka KOROVLJEV , Tijana ŠĆEPANOVIĆ, Ivana MILOV ANOVIĆ: EFFECTS OF GRADED EXERCISE THERAPY ... , 143–154 Figure 1. An overview of the search and selection methodology procedure. Artcles identified from PubMed database Reviewed Abstracts n = 19 Studies included in the research n = 5 Additional titles identified through other sources n = 538 Excluded studies: Other types of fatigue No impact of physical activity Adolescents n = 32 Assessed full-text articles for eligibility and quality n = 15 recovery was compared in a sample of 641 participants over 52 weeks. The average age of the participants was 38 years, with 77% being female. The study included four treatment groups: cognitive-behavioral therapy (CBT), graded exercise therapy (GET), and adaptive pacing therapy (APT), combined with specialist medical care (SMC), as well as SMC alone. Physicians specializing in CFS were responsible for treating participants in the SMC program. Oc- cupational therapists oversaw SMC and APT, clinical psychologists SMC and CBT, and physiotherapists SMC and GET. The primary goal was to determine how many participants in each treatment group achieved complete recovery based on different criteria. Specialist doctors explained the symptoms of the syndrome to the patients and ways to manage their condition, prescribing medications to alleviate symptoms such as pain and insomnia. APT involved carefully matching activity levels to the energy levels of the participants. CBT examined the connection between thoughts and behaviors, encouraging partici- pants to try new ways to cope with their condition. GET gradually increased the volume and intensity of physical activity to improve fitness and reacquaint the body with activity. The method of self-assessment using the standardized CFQ 148 Tamara ZLIČIĆ, Darinka KOROVLJEV , Tijana ŠĆEPANOVIĆ, Ivana MILOV ANOVIĆ: EFFECTS OF GRADED EXERCISE THERAPY ... , 143–154 ANNALES KINESIOLOGIAE • 14 • 2023 • 2 Table 1. Articles Included in the Analysis of the Impact of GET and CBT in the Treatment of CFS. Study Journal Study type 1. White et al., 2013 Psychological Medicine RCT 2. Sharpe et al. 2015 Lancet Psychiatry Pre-post trial 3. Clark et al., 2017 The Lancet RCT 4. Wilshire et al., 2018 BMC Psychology RCT 5. Clark et al., 2021 Journal of Psychosomatic Research Pre-post trial ↓ Sequence number Interventions 1. CBT, GET, SMC, APT 2. CBT, GET, SMC, APT 3. GES, SMC 4. CBT, GET 5. GES, SMC Study sequence number → 1 2 3 4 5 n 641 641 211 641 211 Duration 52 weeks 2 years 12 weeks 52 weeks 12 months Results ↓ fatigue, ↑ physical and cognitive functioning ↓ fatigue, ↑ physical and cognitive functioning ↓ fatigue, ↑ physical and cognitive functioning ↓ fatigue, ↑ physical and cognitive functioning ↓ fatigue, ↑ physical and cognitive functioning, ↑ overall health Legend: n-number of participants; ↓- decrease; ↑-increase; SMC – Specialist Medical Care; CBT – Cognitive Behavioral Therapy; GET – Graded Exercise Therapy; APT – Adaptive Pacing Therapy, GES – Graded Exercise Self-help ANNALES KINESIOLOGIAE • 14 • 2023 • 2 149 Tamara ZLIČIĆ, Darinka KOROVLJEV , Tijana ŠĆEPANOVIĆ, Ivana MILOV ANOVIĆ: EFFECTS OF GRADED EXERCISE THERAPY ... , 143–154 questionnaire was used to measure the participants’ fatigue levels, and the SF- 36 physical fitness assessment scale was used to assess physical and cognitive functionality. The study found the following percentages of participants who met the recovery criteria: CBT: 22%, GET: 22%, APT: 8%, and SMC alone: 7%. When comparing CBT and GET with APT and SMC alone, the chances of achieving recovery were significantly higher for CBT and GET. The next study conducted by Sharpe et al. (2015), a follow-up investiga- tion of the effects of the previously mentioned PACE study was conducted at least 2 years after randomization (Table 1). The aim was to assess additional treatments that participants received after the study and explore whether there were long-term effects in the context of recovery within and between the origi- nal groups exposed to different CFS treatments initially included in the PACE study. Of the 641 participants involved in the original PACE study, 75% of them returned the long-term follow-up questionnaire. Additional treatment had been received by 44% of the participants, with those originally assigned only SMC or APT, as opposed to GET or CBT, being more inclined to seek addi- tional treatment. Improvement in terms of reduced fatigue and better physical and cognitive functionality reported by participants originally assigned CBT or GET methods was sustained in the long-term follow-up compared to one year. Participants initially assigned SMC or APT methods showed improvement in long-term follow-up compared to one year in the context of reduced fatigue and improved physical functionality. To measure the participants’ fatigue levels, the method of self-assessment using the standardized CFQ questionnaire was again employed, and the SF-36 physical fitness assessment scale was used to assess physical functionality. In the study by Clark et al. (2017), the researchers conducted a study called GETSET to investigate the impact of SMC compared to SMC with the addition of the modified Graded Exercise Self-help (GES) method, described in a self-help manual outlining a six-step graded exercise therapy, with an expected duration of approximately 12 weeks. Of the total 211 participants (adults aged 18 and above), 107 were assigned to the GES group, and 104 to the control group. The study aimed to compare the effects of the GES method combined with SMC versus SMC alone in the treatment of chronic fatigue syndrome, hypothesizing that the combined method would yield better results in terms of reducing fatigue and improving physical functionality. With the GES manual, participants had the option to conduct up to four guided sessions with a physiotherapist over 8 weeks, totaling 90 minutes. After 12 weeks, compared to the control group, 34% of the GES group showed 8 points of improvement on the SF-36 physical fitness assessment scale and 3 points of 150 Tamara ZLIČIĆ, Darinka KOROVLJEV , Tijana ŠĆEPANOVIĆ, Ivana MILOV ANOVIĆ: EFFECTS OF GRADED EXERCISE THERAPY ... , 143–154 ANNALES KINESIOLOGIAE • 14 • 2023 • 2 improvement on the CFQ questionnaire, compared to a 14% improvement in the control group. In study number 4 (Table 1), the authors Wilshire et al. (2018) conducted a reanalysis of the previously mentioned PACE study (White et al., 2013), pri- marily focusing on the effects of the GET and CBT methods. They noted that the original authors had not consistently adhered to the procedures outlined in the published protocol, and it is unclear whether the conclusions drawn are entirely justified by the evidence, suggesting that the impact of the applied methods in CFS therapy is limited to self-assessment. After the reanalysis of the self-assessment questionnaire results, the GET group had better ratings for physical function compared to the control group but not in fatigue self-assess- ment, while the CBT group showed better ratings in self-assessment of fatigue but not in physical function. In a study conducted by Clark, McCrone, Pesola, Vergara-Williamson, and White (2021), the long-term effects of the GETSET research in the treatment of CFS were investigated. The aim of this study was to examine the effects of the GES study compared to SMC alone in the context of improved physical functioning and reduced fatigue, with an assessment of the long-term clinical and economic outcomes. Primary outcomes were evaluated through the CFQ questionnaire and SF-36 survey, with questionnaires mailed 12 months after the completion of the GETSET study. In the study, 78% of the participants returned the questionnaires 15 months after the study’s commencement, with previously recorded improvements following GES being sustained in the long- term follow-up but without additional improvement and no significant differ - ence compared to the control group. DISCUSSION Based on the existing research presented in Table 1, the results indicate that the application of GET improves physical functioning and reduces the percep- tion of fatigue more than SMC alone in adults diagnosed with CFS (Clark et al., 2017). It can be stated that the GET method has consistent evidence of benefits in the treatment of CFS, supported by a conducted meta-analysis showing mod- erate evidence of improved physical functionality and reduced fatigue severity (Smith et al., 2015). In clinical practice, GET precedes activities involving ad- aptation, which includes identifying the threshold beyond which the prolonged worsening of symptoms occurs. Subsequently, a ‘pacing’ approach to activities is implemented to maximize the utilization of limited energy reserves (Sandler ANNALES KINESIOLOGIAE • 14 • 2023 • 2 151 Tamara ZLIČIĆ, Darinka KOROVLJEV , Tijana ŠĆEPANOVIĆ, Ivana MILOV ANOVIĆ: EFFECTS OF GRADED EXERCISE THERAPY ... , 143–154 & Lloyd, 2020). Compared to passive controls (such as relaxation or flexibility exercises), GET reduces the fatigue levels at the end of treatment with moder- ate certainty (Larun, Brurberg, Odgaard-Jensen, & Price, 2019). The specific characteristics of the symptomatology of patients with CFS require a prompt adaptation of educational, healthcare, and social systems to prevent issues arising from the current systems (Nacul et al., 2011). In earlier studies, it is noted that the majority of individuals diagnosed with CFS/ME will experience or have already experienced periods when their symptoms relapse or worsen (Clark, 2009). Clark (2009) concluded that it is crucial to have a plan for coping with the return of the symptoms to preserve the progress that has been made and, above all, identifying the cause of the symptom recurrence is essential to reduce the likelihood of it happening again. The reviewed studies collectively contribute to our understanding of therapeutic interventions for CFS/ME within the working population. The PACE study (White et al., 2013) compared vari- ous treatments, revealing that CBT and GET increased the recovery chances significantly. The follow-up study (Sharpe et al., 2015) demonstrated sustained benefits in participants assigned CBT or GET, while those on SMC or APT also showed improvement. The GETSET study (Clark et al., 2017) introduced mod- ified graded exercise self-help – GES alongside SMC, exhibiting superior out- comes compared to SMC alone. Wilshire et al.’s (2018) reanalysis criticized the PACE study’s methodology, highlighting limitations in its conclusions. Clark et al.’s (2021) long-term investigation of GETSET showed sustained benefits but no additional improvement over SMC. CONCLUSION In this study, we underscore the importance of integrating psychological and physical interventions for comprehensive CFS management within the working population. The findings from the reviewed studies, encompassing a combination of CBT and GET, and either SMC or APT, emphasize the signifi- cance of personalized treatment approaches. The consistent positive outcomes of CBT and GET, maintaining their effectiveness in the long term, highlight the critical role of psychological interventions in effectively addressing CFS among the working population. Furthermore, the analysis of the available data and the recommended treatment for CFS/ME indicates that short-term changes can be expected, resulting in a temporary reduction in the sensation of fatigue and an improvement in physical and cognitive functioning (Wilshire et al., 2018). The studies reviewed also revealed a predominant reliance on indirect 152 Tamara ZLIČIĆ, Darinka KOROVLJEV , Tijana ŠĆEPANOVIĆ, Ivana MILOV ANOVIĆ: EFFECTS OF GRADED EXERCISE THERAPY ... , 143–154 ANNALES KINESIOLOGIAE • 14 • 2023 • 2 measurement methods, primarily employing self-reported questionnaires. To address existing gaps, there is a noteworthy need for more research utilizing direct assessment methods, such as biomarkers, providing a direct measure- ment of physiological changes. Previous research (Maksoud, Magawa, Eaton- Fitch, Thapaliya, & Marshall-Gradisnik, 2023) identified potential blood-based biomarkers, encompassing genetic/epigenetic, immunological/mitochondrial/ microbiome, endovascular/circulatory, neurological, ion channel, and physical dysfunction biomarkers. Notably, the use of lymphocytes as a model for in- vestigating CFS/ME pathology is prominent among the immune system-based biomarkers (Maksoud et al., 2023). 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