Patients' experiences with the treatment of long-term fatigue of unclear cause: a qualitative evidence synthesis

Introduction

Chronic fatigue is prevalent in the population and can occur after infections such as COVID-19 or mononucleosis, other life stressors, or without a known cause. Treating this condition is challenging, and there is limited knowledge about patients' own experiences and preferences regarding different treatment approaches. This qualitative evidence synthesis (QES) aims to contribute to the revision of the Norwegian Directorate of Health's guideline for the assessment, diagnosis, treatment, and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The revised guideline will address prolonged fatigue of unclear cause, including CFS/ME, fibromyalgia with fatigue as the main symptom, fatigue resulting from post-COVID-19 syndrome, and other fatigue conditions with unclear cause. Fatigue associated with known conditions (such as stroke, rheumatic disorders, depression, etc.) or as a consequence of treatment (e.g., cancer treatment) is managed within diagnosis-specific pathways and is therefore not part of these guidelines or this review.

Objective

The objective of this QES was to explore patients' experiences with treatment interventions for prolonged fatigue of unclear cause. The relevant interventions include activity-based therapies, rehabilitation measures, psychological approaches, and learning and coping interventions.

Method

The assignment consisted of two deliverables. Deliverable I was an evidence gap map of existing studies in the field. Deliverable II is this QES of patients' experiences with treatment interventions for chronic fatigue. A systematic search for relevant studies and screening of title and abstract were conducted as part of Deliverable I, with the methodology described therein.

We conducted independent full-text screening of studies identified in the research map against our inclusion criteria. Subsequently, we evaluated the methodological limitations of the included studies using a design-specific checklist. Data were extracted from the studies, and the results were synthesized thematically. Finally, we assessed the confidence of our findings using the Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) approach to evaluate how likely the findings are to represent reality concerning the topic and context in which they are to be applied.

Results

The research map included 35 studies. These were screened against our inclusion criteria, resulting in the inclusion of 17 studies in total. The studies involved 306 participants aged 12–74 years and were conducted in the United Kingdom, Norway, the United States, Finland, and Australia. Most studies focused on patients with CFS/ME, while a minority involved long COVID, and one study included patients with various diagnoses, most of whom reported prolonged fatigue. We identified no studies with patients with fibromyalgia, and very few studies on children and adolescents. We identified some research on the experiences of cognitive behavioral therapy (CBT) for people with CFS/ME, but the evidence base for the other interventions was very limited. The findings for most interventions were therefore fragmented and uncertain. For some interventions, no studies were found. However, there were some recurring themes across interventions and patient populations that appear central and important to highlight.

Findings Across Interventions and Diagnoses

Patients valued a holistic approach that acknowledged both the psychological and physical aspects of prolonged fatigue. It was important that the condition was recognized as a real chronic illness (moderate confidence). Many felt that treatments overly focused on anxiety and depression, especially in contexts where stigma around mental health was prominent. Involvement of family and friends in therapy was considered valuable, providing emotional support and better understanding of the patients’ situation (high confidence). Group therapies offered social support and improved understanding of the condition, but large groups could hinder the sharing of personal experiences (moderate confidence).

Tailored and easy-to-understand information about the condition and treatment options was emphasized as crucial, and many appreciated practical tools such as breathing techniques, activity logs, and mindfulness (high confidence). These tools were useful in daily life, although severe symptoms and external factors like work and time constraints often posed challenges. The therapist's knowledge, empathy, and ability to build a supportive relationship were critical for a positive treatment experience (moderate confidence), and realistic expectations of treatment were highlighted as important for engagement. Complementary therapies contributed to coping and improvement for several participants but combining different treatment methods could be challenging. For some, long travel distances to treatment posed a barrier, leading to fatigue and limited participation (low confidence).

Discussion

This review of research on interventions for long-term fatigue revealed a limited and fragmented evidence base. Most studies addressed CFS/ME, while only two studies investigated post-viral fatigue (late effects of COVID-19).

The best-covered interventions were CBT for individuals with CFS/ME, while there were very few studies on the other therapeutic approaches we sought. Studies on experiences with pain reprocessing therapy, amygdala and insula retraining (AIR), hypnosis, meditation, and mind-body processing were missing entirely. We found only one relevant study on pacing, but it had only been published as a preprint and was not included in this review. Many interventions were relatively short-term (ranging from a few sessions to a few months), while the disease course for prolonged fatigue often spans several years, which may limit knowledge on the long-term utility of the interventions.

It is also likely that the most severely ill patients may often be excluded from such studies. Participants included must have a certain level of functioning to take part, making it difficult to generalize findings to bedridden or severely disabled patients. Post-exertional malaise (PEM), a central factor in many patients’ illness experience, is rarely addressed in the studies. This represents a knowledge gap that must be addressed in future research.

The confidence in findings for specific interventions was varied. We had, for instance, moderate confidence in most findings on CBT, while findings on ACT, online coping strategies, and digital consultations had lower confidence due to methodological limitations and insufficient data. For the Lightning Process, we generally had high confidence in the findings, but the evidence was based on a limited number of studies.

A strength of this review is the systematic approach to searching and analyzing the literature, as well as collaboration with experts and stakeholders. However, there are weaknesses, such as the lack of representation of disease severity, socioeconomic status, and cultural factors among the patients, as well as well as the fact that many of the treatments were of short duration.

There is a great need for more research that includes diverse patient groups, addresses PEM, and examines how treatments are experienced over longer treatment periods. To meet patients' needs, it is crucial to prioritize individually tailored approaches, where treatment and support are customized based on the patient’s symptoms, functional level, and response over time. Frequent evaluations throughout the treatment process are necessary to ensure that interventions have the desired effect and do not worsen the condition.

Conclusion

Our findings highlight the need for holistic and interdisciplinary approaches that recognize both the physical and psychological aspects of prolonged fatigue. Support from therapists, family, and peers, as well as access to practical tools, contribute to coping. At the same time, the need for flexible and tailored solutions, including digital alternatives, is emphasized due to challenges such as disease severity, cognitive difficulties, and practical barriers. The evidence base is fragmented, with limited research on the different interventions and few studies including post-viral fatigue, and children and adolescents. There is a significant need for further research exploring how interventions can be adapted to meet the needs of different patient groups.