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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 ZLIČIĆ1, Darinka KOROVLJEV1, Tijana ŠĆEPANOVIĆ1,  
Ivana MILOVANOVIĆ1

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-

mailto:tamara.zlicic@uns.ac.rs


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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 STOPNJEVANE VADBENE TERAPIJE IN ZDRAVSTVENE 
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.



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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-



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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 



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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 



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ANNALES KINESIOLOGIAE • 14 • 2023 • 2

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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 



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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 



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& 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 



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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). However, the heterogeneity shown in many 
of the included studies highlights the need for multidisciplinary research and 
standardized protocols to advance our understanding and management of CFS/
ME. While numerous blood abnormalities show promise as potential biomark-
ers for CFS/ME, none can reliably differentiate individuals with CFS/ME from 
those with other health conditions or those in perfect health (Maksoud et al., 
2023). The variability in findings across studies underscores the necessity for 
multidisciplinary research and standardized protocols. A continual overview 
and the transparent reporting of research methods are essential for developing 
a comprehensive understanding of CFS/ME and refining treatment strategies.

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