Fatigue in patients with syndromic heritable thoracic aortic disease: a systematic review of the literature and a qualitative study of patients’ experiences and perceptions

Abstract

Introduction

The purpose of this study was to explore the literature on fatigue in patients with syndromic heritable thoracic aortic disease (sHTAD), including Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), vascular Ehlers Danlos syndrome (vEDS) and other sHTADs, critically appraise and synthesize the relevant literature. We also aimed to investigate how adults with sHTAD experience and perceive fatigue, and to discuss clinical implications and direction for further research.

Methods

First, a systematic review was performed by searching the published literature in all relevant databases and other sources until 20th October 2022. Second, a qualitative focus group interview study was conducted of 36 adults with sHTADs (LDS n = 11, MFS n = 14, vEDS n = 11).

Results

In the systematic review, 33 articles satisfied the eligibility criteria (3 reviews and 30 primary studies). Of the primary studies: 25 dealt with adults (MFS n = 17, MFS/EDS n = 1, EDS n = 2, LDS/vEDS n = 3, different sHTADs n = 2), 5 with children (MFS n = 4, different sHTADs n = 1). Twenty-two were cross-sectional quantitative studies, 4 prospective and 4 qualitative studies. The quality of the included studies was mostly good, but many had small sample sizes, low response rates and/or participants without verified diagnosis. Despite these limitations, studies indicated high prevalence of fatigue (ranging from 37 to 89%), and fatigue was associated with both health and psychosocial aspects. Few studies found that fatigue was associated with disease-related symptoms. In the qualitative focus groups most of the participants reported that they had experienced fatigue which influenced several aspects of life. Four themes related to fatigue were elucidated: (1) different diagnoses–different fatigue?, (2) the nature of fatigue, (3) searches for causes of fatigue, (4) dealing with fatigue in daily life. The four themes seemed mutually interrelated in terms of barriers, strategies and facilitators for dealing with fatigue. The participants experienced fatigue as a consistent dilemma between self-assertion and inadequacy. Fatigue seems to influence several aspects of daily life and may be one of the most debilitating symptoms of having a sHTAD.

Conclusion

Fatigue seems to negatively impact the lives of people with sHTADs and should be recognized as an important aspect in the lifelong follow-up of these patients. The life-threatening complications of sHTADs may result in emotional stress, including fatigue and the risk of developing a sedentary lifestyle. Research and clinical initiatives should consider rehabilitation interventions aiming at postponing the onset or reducing symptoms of fatigue.

Introduction

Heritable thoracic aortic disease

Heritable thoracic aortic disease (HTAD) is a term that defines a large group of disorder characterized by the occurrence of aortic events, mainly represented by aneurysm or dissection [1]. HTAD can be classified as non-syndromic if the disorder is limited to the aorta, and syndromic when associated to extra aortic features [1,2,3]. Genetic testing is essential since it allows confirmation of the etiological diagnoses for HTAD. An extensive list of human genes and other clinical features associated with HTADs is mentioned in several papers [4,5,6]. Renard et al. [6] found that approximately 53 candidate genes were associated with HTADs, but only 11 genes (COL3A1, FBN1, SMAD3, TGFB2, TGFBR1, TGFBR2, ACTA2, MYH11, MYLK, LOX and PRKG1) were identified as “HTAD” genes as they were assessed as having a “definitive” and “strong” gene-disease association during the curation process [6]. Mutations in the five last genes described above are known as non-syndromic HTAD (nsHTAD), as they are associated with vascular manifestation alone [2, 6, 7]. Mutations in the six first genes are known to cause syndromic HTAD (sHTAD), with systemic manifestations and genetic phenotype, including cardiovascular, musculoskeletal, craniofacial and ocular systems, and cutaneous features [4, 5]. The most common diseases of sHTAD are Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS) and vascular Ehlers-Danlos syndrome (vEDS) [2, 4, 7]. The focus of the present study is sHTAD.

The most serious complications in sHTADs are related to the risk of aneurysm and dissection of aorta and other large arteries [2]. Life-threatening complications can require emergency intervention, with increased risk of morbidity and mortality [2, 8]. Because of the risk of aortic dissection, many patients are advised to refrain from contact sport, to limit their physical exertion and to control their blood pressure strictly [9, 10]. Unfortunately, they often follow by a sedentary lifestyle [10,11,12,13]. Many have skeletal signs with hypermobile joints, chest deformities and scoliosis [4,5,6]. Physical impairment, chronic pain and fatigue associated with sHTADs may be exacerbated by the fact that most sHTADs have no effective treatment or cure [2, 4, 14]. Living with a sHTAD may be vastly more complex than just its medical features [15,16,17,18]. Many aspects of an individual`s life may be affected such as family life, education, work-life and leisure activities [13, 19, 20].

Rationale for the study in the context of what is already known

In recent years, fatigue has increasingly been studied in genetic conditions, and recognized as an important clinical factor affecting several aspects of patients’ lives [21]. Through our work in a resource center for rare diseases, we frequently encounter patients who report fatigue as a serious problem. Many patients also experience lack of understanding and support from professionals regarding their fatigue. There is a risk that health professionals do not pay attention to fatigue because it is overshadowed by other more potential life-threatening aspects of the disease. Often, medical causes of fatigue may be ignored [21].

A challenge is that fatigue is a complex phenomenon lacking a clear definition. Many studies fail to explain their definition of fatigue [21, 22]. Authors often do not explicitly define fatigue, but rather imply its meaning by the concept associated with the instrument used for measuring fatigue. Other terms used in the literature for fatigue included “tiredness”, “exhaustion” or “lack of vitality” [23]. A common definition of fatigue is “an overwhelming sense of tiredness, lack of energy and feeling of exhaustion, mental, physical or both” [24]. Other attempts to classify fatigue according to the affected domains are (motor versus cognitive) or the presumptive origin (central versus peripheral) [25]. Penner et al. [25] have proposed a unifying taxonomy that discriminates between fatigue (in sense of self-perception) and performance (fatigability). Self-perceived fatigue can be quantified by scales that cover physical, psychosocial and/or cognitive aspects, whereas fatigability can be quantified by measuring the decline in performance of given tasks (such as motor fatigability and decline reaction time, often measured in laboratories) [22, 25]. In this study, the focus is on self-perceived fatigue.

There is a wealth of distinct and often discrepant scales that have been designed to measure both generic and disease-specific fatigue [21, 23]. To the best of our knowledge, no disease specific scales have been developed to measure self-perceived fatigue in persons with sHTADs. Brown et al. [26], Penner et al. [25] and McCabe et al. [27] have described vitality as the opposite of fatigue, with a low degree of vitality indicating severe fatigue. The RAND version of SF-36 Health Survey [28] is a health related quality of life measure where the subscale of vitality is defined as a scale for measuring general energy, lack of vitality, i.e. similar to fatigue [26, 27, 29] 36-Item Short Form Survey (SF-36) Scoring Instructions | RAND. Vitality is found to strongly correlate with different validated measures of fatigue [26, 27]. Vitality can also be used to assess a general level of fatigue in the preceding 4 weeks [29]. Overman et al. [29] indicate that the scores of 35 and lower of the SF-36 vitality score (0–100) indicate severe fatigue. We therefore included studies with outcomes on SF-36 vitality (SF-36vt) in the review part of this study.

In chronic diseases, fatigue may have multiple contributing factors e.g. sleep disorders, pain, reduced physical activity, depression and pharmacotherapy [25, 30]. As complex disorders, there are numerous factors in sHTADs that could interfere with physical, psychological and social function [31]. It is hypothesized that a number of factors may cause fatigue in patients with sHTADs such as physical (cardiovascular and respirators factors, working capacity, use of beta-blockers, reduced visual acuity and joint hypermobility), and mental/psychological comorbidity (cognitive dysfunction and psychological distress) [13, 16, 17, 19, 20, 31, 32]. The research on prevalence, associations, patient experiences and impact of fatigue in sHTADs appears to be fragmented and not well known. We therefore decided to undertake an overview of the literature and combine it with a qualitative study of the patients’ perceptions and coping strategies regarding self-perceived fatigue. We did this in the hope of developing a more evidence-based clinical practice.

The aims of the study

• 1. To identify, critically appraise and synthesize available research about self-perceived fatigue in sHTADs.

• 2. To investigate the experiences and perceptions of fatigue in adults with different sHTADs.

• 3. To investigate key concepts of fatigue, identify knowledge gaps, and discuss clinical implications and direction for further research on fatigue in sHTADs.

Methods and materials

Systematic review

Study design

Owing to the limited number of studies on fatigue in sHTADs, all studies stating that at least one aim was to study fatigue in sHTADs were included in the review. The review was conducted according to the recommendation for systematic reviews [33, 34], and PRISMA checklist for systematic reviews [35] (Additional file 1). Each study was examined independently [33, 34, 36]. Standardized specific criteria were used to critically appraise the different types of studies [37,38,39]. In the evaluation of knowledge on fatigue, only the fatigue part of the studies was addressed. The review protocol is included in Additional file 2.

Search strategy

Systematic searches were conducted on relevant literature until October 2022, in PubMed, CINAHL, Embase, Ovid, MEDLINE, the Cochrane and Google Scholar. First, we conducted a search of terms related to HTAD, resulting in 15,872 hits. Then, we conducted a search of terms related to fatigue, resulting in 9547 hits. Third, we combined the two searches, resulting in 845 hits after duplications were omitted. We also examined the citations in the papers that were obtained, and conducted searches in Open grey literature (OpenGrey, PsycEXTRA and Home—ClinicalTrials.gov), resulting in 22 papers. Experts with clinical experiences and scientific publications on pain, fatigue or other relevant aspects of sHTADs were asked, but no additional papers were found. The search terms and search strategy is described in Table 1.

Table 1 Search strategy

Eligibility criteria: Articles were considered for inclusion if they investigated fatigue in sHTADs. The eligibility criteria were developed based on preliminary review of a random subset of relevant fatigue studies, a scoping review of fatigue in rare diseases [21], as well as theoretical literature about the concept of fatigue. The three basic inclusion criteria were as follows: (i) all individuals affected by a specific sHTAD as defined in the search criteria. Studies with mixed population including sHTADs that did not report subgroup analysis were excluded; (ii) all types of studies, peer-reviewed articles presenting own results, published in English, French, German, Norwegian, Danish or Swedish language; and (iii) where the aim and outcome of the studies “included examining self-perceived fatigue or vitality, and/or predicting variables or factors associated with fatigue/vitality in sHTADs” as a primary or secondary outcome.

No exclusions were made on the basis of age, gender or ethnicity. Unpublished data or case-report, conference abstract, posters, letter to editors, expert opinions, guideline, unpublished data and study protocols and studies with less than six participants were excluded.

Selection of publications

Two researchers (GV/HJ) independently reviewed the abstracts and/or articles from each publications that was identified through the search strategy described above. When considered potentially eligible, the full text of these studies was obtained and reviewed by the same two researchers against the eligibility criteria to determine their eligibility. A third (TB) and fourth researcher (AMG) verified the articles inclusion or exclusion in accordance with the final eligibility criteria.

Handling data, critical appraisal and data extraction

All included articles were screened and categorized independently by three researchers (GV, HJ, TB) on the basis of the content of the article [36, 39, 40]. Discrepancy and disagreement were discussed and resolved by involving a fourth researcher (AØG). The studies were first categorized according to which sHTADs the study dealt with. Specific validated criteria were used for critical appraisal of quantitative [39], qualitative [41] and review [42] articles. Seven criteria were used to evaluate the quantitative studies: (i) sample size (ii) sample representativeness (iii) control group (iv) the validity of the measurement (v) drop-out/missing data (vi) blindness and (vii) credibility assessment [39]. No controlled trials or randomized controlled trials (RCT) were found; therefore, the criterion about blindness was omitted. Six validated criteria were used for assessing the qualitative studies [41] and seven criteria for assessing reviews [42]. In addition to the validated criteria (questions) for critical appraisement of the different types of studies, we added two criteria (questions): To which degree the papers discussed the limitations of the study and the extent of contribution on new results about fatigue/vitality in sHTADs. Because of the complicated process leading to the diagnosis of sHTADs, we also collected information from the included articles about their use of diagnostic criteria and/or genetic testing to identify their study population. The quality assessment criteria for quantitative, qualitative and review studies and the justifications for the assessment of each article are reported in Additional file 3.

The studies were too heterogeneous to perform statistical pooling and meta-analyses. Therefore we performed a narrative synthesis of the findings, taking into account methodological quality and analytic rigor in the examination of the reported findings [42, 43].

A mixed method thematic analysis was conducted to structure and depict all variables involved in the reviewed studies [44]. All included articles were screened and categorized independently by two researchers (GV/HJ) on the basis of the of the content in the articles. Discrepancy and disagreement were discussed by involving a third (TB) or a fourth (AØG) researcher. Information was extracted on study population, diagnoses, recruitment sources, study designs, methodology, fatigue measurements and other validated instruments, key predictor variables, main results and authors’ conclusions. Each study was categorized according to whether fatigue/vitality was the primary (major) or secondary outcome. Using a matrix [44, 45] the key features were summarized and synthesized. The relationship between variables and between different levels and groups of variables (main-/sub-variables) were indicated. A mixed-methods approach [44] was used to integrate the conclusions from the qualitative and quantitative strands (comparing, contrasting building on or embedding with the other) in order of to provide a fuller understanding of fatigue in sHTADs. Finally, the results of the articles were synthesized and summarized in three different main themes (i) the prevalence of fatigue in sHTADs (ii) the associations/predictors of fatigue and (iii) fatigue in children and adolescents with sHTADs.

Qualitative focus group interviews

The qualitative focus group study has been approved by the Regional Committee for Medical Research Ethics (Health Region South-East) (2017/745). The study was conducted according to the COREQ-checklist for qualitative research [46]. We have previously published an article with comprehensive description of methodology of the focus group interviews [12], therefore only a brief summary about the methodology is presented in this paper.

Study design and informants

Patients with a confirmed diagnosis MFS, LDS and vEDS, registered at TRS National Resource Center for Rare Diseases in Norway were eligible and were invited to participate between October 2017 and April 2018. A combination of convenience and purposive selection method was used. The intention was to include approximately 36 patients, as this was considered appropriate to capture unique variation and saturation of the data.

Strategies for ensuring trustworthiness and credibility

Three researchers (GV, HJ, TB) ensured trustworthiness and credibility throughout the data collection and analysis process [46, 47]. The study reporting adheres to the consolidating criteria for reporting qualitative research [46], and the Standards for Reporting Qualitative Research [47].

Procedures and analyses

A semi-structured interview-guide was developed as a framework for the focus group interviews. The interviews lasted for an average of 110 min (range 90–120 min) and were audiotaped and transcribed verbatim by two researchers (GV/HJ). An Inductive Systematic Text Analysis (ISTA) was conducted [48, 49]. To ensure the robustness of the study we followed the principles of Malterud [48, 49] of six step-by-step analysis (Additional file 4), based on the four criteria of credibility, dependability, confirmability and transferability [47, 49, 50]. Two researchers (GV/HJ) independently conducted the preliminary analysis and compared preliminary results. To assess the interpretative rigour of the analysis, we assessed inter-coder agreement to control the coding accuracy and monitor inter-coder reliability. Differences were discussed in an iterative process until consensus was reached among the research team (GV, HJ, TB, AØG).

Results

Systematic review results

Search results

The search strategy is presented in the flow chart in Fig. 1. A total of 867 articles were identified, 251 were read full text, of these 33 articles satisfied the eligibility criteria and were included in this review. There were 30 primary and three secondary (review) studies.

Fig. 1

Flowchart of search, screening and inclusion process of the systematic review

Included secondary studies: review articles

Three review articles fulfilled our inclusion criteria [19, 20, 51], but in no reviews the primary outcome was fatigue. Two review articles dealt with psychosocial aspects of MFS. One [20] included 11 articles dealing with fatigue, and the other [19] four articles. The last review article [51], addressing quality of life (QoL) in people with HTADs, included five articles of fatigue. All three review articles indicated that fatigue appears to be prevalent in patients with sHTADs, but none reported the estimated prevalence of fatigue of included studies. Nevertheless, all reported that fatigue in patients with MFS seems to have a huge impact on their QoL and daily life.

Included primary studies: fatigue in sHTADs

Of the 30 primary studies dealing with fatigue in different sHTADs, 25 dealt with adults while five with children/adolescents. Twenty-one articles on patients with MFS (17 on adults and 4 on children), one article on MFS and EDS, two on EDS, three on vEDS/LDS, and three on different sHTADs (two on adults/one on children). One third (n = 10) of the studies [52,53,54,55,56,57,58,59,60,61] did not describe if they included patients with verified diagnoses. The diagnoses were either self-reported or the confirmation of diagnoses was not reported in the study. The rest of the studies either included patients diagnosed according to the Ghent Nosology for MFS, or genetic verified diagnoses for LDS, vEDS and the other sHTADs. Eighty-three percent of the articles were published from 2010 to October 2022, with 70% published from 2015 onward. Twenty-three articles (77%) were from Europe, six (20%) from USA, and one (3%) from Korea (Table 2).

Table 2 Data extraction of included studies of patients with sHTADs

Methodological appraisal of primary studies

Study design and level of focus on fatigue: Of the 30 primary articles 22 studies were cross-sectional quantitative questionnaire studies [11, 13, 16, 17, 31, 32, 52,53,54, 56,57,58, 61,62,63,64,65,66,67,68,69,70]. Four were prospective: one pilot rehabilitation intervention study [71], two experimental studies [55, 72] and one longitudinal study [73]. Four studies were qualitative and used different methods: individual interviews [74], focus groups [12], document analyses [59] and combining individual interviews with focus groups [60]. Three of the qualitative studies dealt with children/adolescents [59, 60, 74]. No randomized controlled studies were identified.

In only eight [16, 17, 31, 32, 55, 57, 61, 68] of the 30 articles the primary outcome was to investigate fatigue. All these were cross-sectional quantitative studies. Four were on MFS, two on EDS, one on vEDS/LDS, and one on children with different sHTADs (MFS, vEDS) (Table 3).

Table 3 Quality assessment om included studies; quantitative studies, qualitative studies and review studies

Recruitment and sample sizes: In most papers [11,12,13, 16, 17, 31, 32, 52, 55, 58, 60,61,62,63, 65,66,67,68,69,70, 72,73,74] the participants were recruited from the clinic where the researchers worked, and in some [54, 56, 57, 59, 64] from the patient organization, or from both [53, 71]. Approximately, a total of 2,479 adults were included in the articles, with a variation of 16 [31] to 318 [54] respondents (mean 94/median 64), and in most studies the response rate was low. Four studies had more than 200 participants [54, 57, 63, 64], but the sample size of these studies probably represents a small percentage of the estimated national patient populations. In the largest study [54], the diagnosis was self-reported and the link to the survey was sent to 13,280 persons, of whom 318 completed the survey, indicating a response rate of 2% of the study population.

Instruments for assessing fatigue and vitality

Ten studies [11, 16, 17, 31, 63, 66, 67, 69, 71, 72] used Fatigue Severity Scale (FSS) two [55, 68] used Multidimensional Fatigue Inventory (MFI-20), two [32, 57] used Checklist Individual Strength (CIS), one [31] Fatigue Questionnaire and one [54] Quality of Life index. Eleven studies [13, 56,57,58, 62,63,64,65, 68, 71, 73] used SF-36 and one [52] used SF-12. Two studies [53, 64] used study specific questions to measure fatigue. Some studies [31, 57, 63, 64, 68, 71] combined two measurements. In studies of children, one study [70] used Patient Reported Outcomes Measurement Information System (PROMIS) and the other [61] Fatigue 10a Paediatric v20 short form. Table 4 shows an overview of the instruments used in the studies measuring fatigue and vitality.

Table 4 Instruments for assessing fatigue used in the different studies

Control groups: Four papers [32, 57, 58, 61] compared the results of fatigue with normative data and subgroups, three [7, 56, 65] with healthy controls matched for age and gender, three [13, 16, 17] with normative data and other diseases, six [31, 52, 53, 64, 68, 70] only with normative data. Two prospective studies [71, 73] included pre-/post results and normative data. Seven studies [11, 16, 54, 62, 63, 66, 67] did not describe any comparison group. There were large variations in the use of control groups and comparison to the general population and to other patient groups. None of the qualitative studies compared the results with normative data or other groups.

Limitations and credibility: Most studies (83%) had thoroughly described factors (confounders) that may negatively impact the credibility of the study, while three studies [13, 31, 62] had very limited description and two studies [64, 66] had no description of limitations. Omitting information about the study`s potential limitations may decrease the credibility of the study. The lack of credibility was also assessed related to other factors such as lack of verified diagnoses, small samples, limited transparency of the selection, methodology and analyzing process, the use of advanced statistical analyses in small sample sizes, no assessment of the validity and reliability of the measurements, low response rate and no drop-out or no non-response analyses. In addition, in qualitative studies, taking the role of the researcher into account and discussion on how researchers’ preconceptions may influence the results are important strategies for ensure trustworthiness and credibility of the study. (More detailed information about the assessments and justifications are available in Additional file 3).

Despite the included studies on fatigue in sHTADs being of limited in size, the overall quality of the methodology ranged from very good to fair, with most studies being rated as good. The credibility of a study combined with its results were used to decide how each study was assessed in contributing new knowledge about fatigue in sHTADs.

Synthesize and summary of results from included articles

Prevalence of fatigue and decreased vitality in adults with sHTADs: Several studies [13, 16, 17, 32, 53, 55, 57, 58, 62, 64, 72, 73] presented increased fatigue (or decreased vitality) in adults with sHTADs compared to the general population, but the variation on prevalence of severe fatigue varied from 37% [32] to 88.5% [53] in MFS. Prevalence of severe fatigue in LDS was 58% [11, 16, 69] and 42% in vEDS [11, 16, 69], but these results were reported from the same study cohort. Comparing prevalence values was hampered by the fact that different instruments and cut of values were used for severe fatigue. Figure 2 shows the mean score of the different studies reported outcome on Fatigue Severity Scale (FSS). Four studies were not included in Fig. 2 because they reported results from the same study cohort as two studies illustrated in the figure. Higher fatigue scores signify more fatigue.

Fig. 2

Mean Fatigue Severity Scale score in different sHTAADs

Prevalence of fatigue/reduced vitality was not reported in studies using SF-36. Figure 3 illustrate the mean score (+ 1SD) of the included studies reporting SF-36vt mean (SD). Very few studies indicated severe fatigue in adults with sHTADs according to SF-36vt scores of 35 and below [29], but results varied.

Fig. 3

Mean SF-36 vitality score in the different sHTAADs

Some studies also compared their results to other diseases. Bathen et al. [17] found that adults with MFS had higher prevalence of fatigue than patients with rheumatoid arthritis, but lower than for other chronic conditions. Rand-Hendriksen et al. [13] found that the MFS study cohort scored lower of SF-36vt scores than all included comparison groups (hypertrophic cardiomyopathy, cystic fibrosis, Bechet’s syndrome). Rand-Hendriksen et al. [13] indicated that the low vitality score may reflect the common complaint of fatigue and reduced physical endurance among persons with MFS.

Associated factors to fatigue in adults with sHTADs: Many articles reported variables associated with fatigue and/or vitality. Fatigue was found to be positively associated with pain [16, 17, 32, 57], disability [31, 57, 61, 72], cardiovascular problems and multiorgan burden [16], sleeping problems or hyper somnolence [16, 56, 68], orthostatic intolerance [55], and psychological factors [16, 31, 32]. One study [53] indicated positive associations between fatigue and use of beta-blockers, while three other studies [17, 31, 55] found no such significant associations. One study [32] found that patients using losartan had less fatigue compared to those not using losartan. Factors associated with fatigue in sHTADs appear to be somewhat inconsistent, particularly about the association between medication and fatigue.

Fatigue was also found negatively associated to physical activity [11], work participation [17, 64, 66, 67, 69] and quality of life [54, 63, 65, 67, 69, 71], and positively associated to being female [31, 32, 58]. Only one qualitative study [12] was identified reporting some results on fatigue in adults with sHTADs. This study mainly focused on physical activity, but described that adults experienced it difficult to cope with fatigue in daily life. Fatigue and less physical activity seem to have a mutually reinforcing negative effect [12].

Several studies also reported other aspects of fatigue. Rao et al. [64] noted that fatigue was ranked as the third highest disease concern, while cardiac and spine problems were ranked first and second. This study also emphasized that MFS patients experienced specific difficulties in executive functions such as mental fatigue, leading to diminishing QoL. Severe fatigue seems to significantly heighten the perception of their condition`s severity, and experienced psychological distress may also increase fatigue [31, 32, 53, 54]. Interestingly, one pilot experimental intervention study [71] measured pre- and post-intervention fatigue and found that a three-week rehabilitation program significantly decreased the extent of fatigue in patients with MFS and LDS one year post-intervention. Several studies expressed the need for a specialized in-hospital rehabilitation program to deal with fatigue and other symptoms related to the disease.

Fatigue in children with sHTADs: The study samples of the five articles dealing with children and adolescents varied from 19 (74) to 147 (59) participants. Approximately, a total of 342 children and adolescents were included.

The results from the five studies [59,60,61, 70, 74] on children and adolescents with sHTADs are not consistent about the prevalence and extent of fatigue. One study [71] found that 44% of children with MFS reported fatigue sometimes or often. Another [61] found that children with MFS had less fatigue compared to the age matched norm data, and significantly lower prevalence of fatigue than children with hypermobile EDS. In the study [59] of adolescents with MFS on social media, fatigue was seldom not mentioned as a problem when discussing problems related to the diagnosis. Few studies had examined factors that are associated with fatigue in children with sHTADs, but one study [61] found that fatigue was significantly associated to disability and pain. Two qualitative studies [60, 74] reported that children and adolescents with MFS experience fatigue that limits school participation in sport and other activities. Children also described difficulties keeping up with their peers, feeling being different and therefore avoid social activities. This indicates that fatigue seems to be prevalent in children with sHTADs. However, the results were not consistent and more research is warranted.

Results from the qualitative focus group interviews

Participants

A total of 36 individuals with sHTADs (14 with MFS, 11 with vEDS and 11 with LDS) participated in the focus group interviews. The participants represented a variety of diagnoses, gender, age, education and social backgrounds. The characteristics of the participants is shown in Table 5.

Table 5 Characteristics of the participants in focus groups

Themes and categories

Four main themes emerged from the analyses: (1) Different diagnosis–different fatigue? (2) Nature of fatigue (3) Searching for causes of fatigue (4) Dealing with fatigue in daily life. Overall fatigue was described as an overwhelming phenomenon, with an unpredictable character, and a feeling that fatigue dominated and controlled most life-situations. This is illustrated by the following quote:

“I really don’t know what to do, I never know and have no control, so for me fatigue is dominating my life” (an elderly woman with LDS).

• 1) Different diagnosis—different experiences of fatigue?

The focus groups were divided according to the diagnostic groups (2 groups with MFS, 2 groups with LDS and 2 groups with vEDS). No distinct differences emerged between the participants in the different disease groups on how they experienced and describes fatigue. They described that fatigue can be difficult to describe and explain, and many had rarely talked about it seriously before. Therefore, they emphasized that data collection with focus groups seemed to be constructive since it gave them opportunity to recall and confirm aspects with peers and share experiences. Most participants in all six focus groups reported that they experienced periodic or permanent fatigue, and there were no differences between the diseases. Despite the fact that having a sHTADs may be life threatening, many described fatigue as one of the most debilitating symptoms of the diagnosis. The following quote cover this on an overall level:

“I barely notice the severe symptoms of this diagnosis and sometimes I just forget it. But I get so tired of always being tired” (young man with vEDS).

• 2) Nature of fatigue—how do they experience fatigue?

Many of the participants experienced that fatigue was a combination of a bodily sensation and a foggy feeling. They described an overwhelming feeling of tiredness, and that parts of their body was heavy or paralyzed. Some described that their legs felt like lead, and they had trouble with moving. A misty feeling was described as having a glass bowl around their head, including brain fog. They felt it hard to concentrate, speak, listen or sort out impressions. Many described that it interfered with concentration at work and social interaction. The character of fatigue was also described as unpredictable, controlling their life, and being impossible to resist and combat.

“Yes, it’s weird, because I’m so incredibly tired. I can’t leave my bed, because my legs will not move, and my brain feels so foggy and I can’t think and talk right. This is not me… and I don’t know why” (woman with MFS).

• 3) Searching for causes of fatigue

Many expressed frustrations of neither knowing the cause of fatigue nor how to deal with an inexplicable exhaustion. Searching for biomedical and other reasonable reasons of fatigue was common. Some claimed that being hypermobile requires more body energy for stabilization of joint and muscles. Medication and use of blood pressure medicine was also mentioned as a possible explanation for fatigue. Others described how chronic pain and constant worrying about the life-threatening aspects of the condition for both them and family members made them exhausted. Many also described that being physically active and doing exercise was challenging, but despite that, exercise was emphasized as important in counteracting fatigue. Some mentioned also that physical activity was associated with anxiety and insecurity, due to the difficulties of finding the right balance between healthy and unhealthy activities. Avoiding physical activity was therefore a coping strategy for some, resulting in a negative spiral of inactivity, more fatigue and a sedentary life.

“I wish I had known the reason for my fatigue, it had been much easier to know what to do and combat it” (young man with LDS).

Another aspect many of the participants described as challenging was the suspicion and lack of understanding from other people about the phenomenon fatigue. When participants tried to convey the gravity of their experiences to others, they were not always understood. Participants described this as exhausting and it increased their uncertainty about the fatigue symptoms. This, in turn led to feeling of guilt, inadequacy and an inner struggle of their desires and what they could achieve.

“It is so invisible and common, everyone is exhausted sometimes… so people might understand in their own way… but they really don’t understand the reality of having “real fatigue” (middle aged woman with MFS).

• 4) Dealing with fatigue in daily life

Most of the participants described that fatigue impacted different aspects of daily life, such as family life, employment, and social life. Some emphasized that they had learned to cope with fatigue by energy economizing and prioritizing between different aspects of life. They realized that fatigue was not dangerous, but only frustrating and debilitating, and some tried to accept it as part of their illness. Others described that avoiding important life events because of exhaustion, was part of their daily choices. Difficulty of dealing with fatigue in the work situation was emphasized as a common challenge. With an overwhelming feeling of tiredness, it was impossible to fulfill their obligations as employees. For some, early retirement was the only solution. Others described attempts to strive to maintain full employment and trying to keep up the pace in what they perceived as a “normal life”. They used all their energy at work, which affected both family life and leisure activities. For some the long-term effect of keeping up the pace was increased fatigue because they were not able to rest enough. Others had found strategies for dealing with fatigue in the work life, particularly those who had informed their employer about their condition. More flexible work conditions and agreements with their employers, made it possible to maintain work ability, despite fatigue.

“For me, work is of invaluable value, I appreciate it so much, it gives me energy but it can also drain me of energy, so it is important to be aware and pay attention. Fatigue is so difficult to handle” (middle-aged man with MFS).

Discussion

Systematic review of relevant research of fatigue in patient with sHTADs

Identified research

Aim one was to identify, critically appraise and synthesize the research of self-perceived fatigue in sHTADs. We identified 33 articles dealing with fatigue in sHTADs, 3 reviews and 30 primary articles, but in only 8 articles, the primary outcome was to investigate fatigue. The results indicate that the amount and extent of studies on fatigue in sHTADs is very limited. Most articles included patients with MFS, presumably because MFS is more common and better known than the other diagnoses. The prevalence of these diseases worldwide is highly uncertain. Prevalence of MFS is estimated to be 10 per 100,000 [75, 76], and prevalence of vEDS is estimated to be 0.5–2 per 100,000 [77], while prevalence of LDS is unknown but probably much lower than for MFS [78]. The prevalence of the other sHTADs is even lower [5, 6]. Over the past two decades, there has been exponential increase in genetic research on pathogenic variants explaining sHTADs [1, 5, 6]. The increased focus on diagnostics, survival and treatment may have deflected clinical attention away from patient`s less dangerous symptoms, such as fatigue. LDS is a relatively new diagnosis, and first described in 2005 [4, 79]. Most studies of LDS concern medical aspects related to the diagnoses. Because most of the symptoms of MFS are overlapping with symptoms of LDS, vEDS and other sHTADs [4,5,6], it seems likely that fatigue impacts these patient groups similarly, although the pathophysiological mechanisms of fatigue may be different.

Critical appraisal of included articles

Most studies used quantitative cross-sectional questionnaire design, besides four prospective and four qualitative studies. The identified articles and results consistently were based on small sample sizes and/or low response rates. The respondents were mainly recruited from the clinic where the researchers worked or from patient organizations. These recruitment strategies yield a risk of bias for recruiting motivated persons with particular medical problems. Thus, the findings may be different from the non-respondents and therefore represent a bias related to the total population. Nearly all the patient populations lived in Western developed countries; Europe and USA or Korea. As cross-cultural differences of fatigue have been found in several studies [80], more research from other countries and cultures is warranted.

Nearly all quantitative questionnaire studies (cross-sectional and prospective) used standardized instruments with generic scale design, besides two papers using study specific questions about “fatigue being present or absent”. The use of standardized instruments can provide quantitative indication of fatigue level, but incompletely reported results, use of different instrument and use of different cut of values for severe fatigue made meta-analyses or statistical pooling difficult. Such meta-analyses could have been useful for clinical practice. The huge variations in prevalence of fatigue and vitality score within and between the different sHTADs may reflect differences in study design, recruitment routines, methodology, and national differences in cultures and perceptions. The representativeness and generalizability of the results may be questioned; however, a strength was that the methodology of included studies was commonly rated as good, and that most emphasized and discussed limitations of their study. This in turn, increased the credibility of the studies.

Synthesis of the literature

The prevalence of fatigue: The results from the reviewed papers are equivalent when indicating that adults with MFS have vastly higher prevalence of fatigue than the general population; and it is likely that individuals with sHTADs may experience a significant impact of fatigue on daily life. This is in accordance with reports of fatigue in other severe conditions such as systemic sclerosis [81], multiple sclerosis [82], and cancer [83].

Fatigue seems to be complex and can occur as primary or secondary symptom, as well as a comorbidity of an underlying disease [31, 68, 78]. Disentangling the origin and nature of fatigue in patients with sHTADs may be challenging. Several studies [13, 16, 31, 53, 55, 56] hypothesized that the biomedical aspects of sHTADs such as cardiovascular and respiratory factors, reduced visual acuity and joint hypermobility may impact fatigue, but only a few studies found such associations.

Fatigue has also been described as a well-recognized side-effect of blood pressure medicine [84], but the results from the included articles were contradictory. Only one [53] study found that medication was associated with more fatigue, while three studies found no such associations in patients with sHTADs. Interestingly the study of van Andel et al. [32] found that the use of losartan was associated with decreased fatigue. The effect of losartan on fatigue may be an under-researched aspect in these patient groups, and the limited and conflicting literature reveals that more research is needed. Our results also indicate that clinicians should be aware that fatigue may be exacerbated by the use of medication, and should enquire about the effects of medication on fatigue when assessing and prescribing new medications.

Chronic pain was also found to be significantly associated to fatigue in the included articles, similar to reports [85,86,87] on others chronic diseases. Pain in patients with sHTADs [14,15,16, 18] may contribute to lower energy level and lower sense of well-being [64]. One explanation is that chronic pain negatively influences sleep quality, and less sleep can decrease one`s pain threshold and pain tolerance as well as intensify the pain, thus exacerbating sleep problems, and thus increasing fatigue [87, 88].

Another aspect that emerged from the included articles was the close connection between physical activity and fatigue. Patients with sHTADs are often recommended physical restrictions because hemodynamic changes and increase in blood pressure are associated with an enhanced risk of aortic growth and acute aortic dissection [10, 88]. However, they are also recommended to be physical active. Total absence of physical exercise is deleterious and may lead to muscle wasting, joint stiffness, and problems with social and professional reintegration, depression and fatigue [10,11,12, 88]. Lack of exercise and deconditioning can cause tiredness and exhaustion. Finding the right balance between safe and unhealthy exercise for these patient groups can be a major problem [12]. Patients may experience anxiety related to physical activity, which in turn may lead to a sedentary lifestyle and more fatigue [9, 11, 12, 53, 89, 90], with these effects probably being negatively mutually reinforcing [91]. There are promising results that exercise-based cardiac rehabilitation in MFS and LDS can help these patients to decrease fatigue and chronic pain, with increased physical endurance and quality of life [71]. More clinical research, including more knowledge-based practice and rehabilitation guidelines for patients with sHTADs seems to be needed.

Fatigue in children and adolescents: Research on fatigue in children with sHTADs is very limited and the results varied. In three studies [60, 70, 74], fatigue was reported to create challenges in daily life, while in another [61] children with MFS reported less fatigue than healthy controls. One study [59] also indicated that fatigue was nearly not mentioned on social media when young people shared experiences about MFS. Nevertheless, more information about the prevalence, associations and experiences of fatigue in these pediatric groups is needed. Studies of children with other chronic diseases have revealed that fatigue negatively impact QoL [92], so quantifying fatigue in children with sHTADs may be critical. Understanding the impact of fatigue may be the first step for improving the quality of life for these groups.

Focus group interviews combined with results from the review part

Aim two was to investigate the experiences and perceptions of fatigue in adults with different sHTADs. In the focus group interview, we did not measure the extent of fatigue, but our impression was that nearly all of the participants reported that they experienced fatigue. Participants in the focus group interviews emphasized that fatigue is one of the most debilitating symptoms of having a sHTAD, similar to the results from several of the studies from the review part. Fatigue seems to cause significant levels of distress, and the unpredictability and invisibility of the symptoms were emphasized as particularly challenging. Not being taken seriously and constantly being misunderstood was also highlighted as challenging and negatively affecting their self-esteem and self-understanding. Another challenge was to combine fatigue with the ability to work. Fatigue was reported to be the most prevalent reason for early retirement in the some of the included articles in the review [16, 17, 19, 66, 67].

Both in the review part and the focus groups it emerged that the subjective perception of the disease may have substantial impact on how people cope with fatigue [53, 64]. The physical severity of sHTADs has been discussed [13, 31], and in most papers, severity appears to be mainly associated with the cardiovascular manifestations [13, 53, 67]. The cardiovascular manifestations may be underestimated in both adults and children as long as the individuals experience no subjective complaints. The subjective severity seems to be mainly determined by the disease manifestations that is perceived by the patients or caused physical disability. The differences between physical severity and subjective severity may indicate that the patients perceive the disorder differently from the professionals. This is important for health care professionals to recognize when dealing with fatigue in these patient groups.

Overall, the results from our study indicate that the perception of fatigue is probably not an isolated problem, but rather a combination of factors related directly to the disease and psychological stress factors and indirectly to the lack of psychosocial support and the complex response of having a rare chronic disease. Based on these results, it is difficult to determine how widespread severe fatigue is among adults and children with sHTADs. Studies combining qualitative approaches with quantitative measurements such as FSS, MFI-20, CIS or other validated measurements could provide valuable information on both prevalence, associations and experiences of fatigue in these patient groups.

Clinical implications and direction for further research

The third aim was to investigate key concepts of fatigue, identify knowledge gaps, and discuss clinical implications and direction for further research on fatigue in sHTADs.

The research on fatigue in the different sHTADs is limited, particularly in other sHTADs than MFS. Our results indicate that the concept of fatigue can be described in relation to its physical, cognitive, emotional and social impact. Further research in sHTADs can attempt to examine the concept of fatigue and unifying the taxonomy of discrimination between fatigue in sense of self-perception and performance (fatigability). This may help to clarify the complexity of the phenomenon. The negative consequences of fatigue seems to be consistent across sHTADs, as is the uncertainty concerning its underlying pathophysiological mechanisms. Therefore, more research about pathophysiologic mechanisms in sHTADs and other causes of fatigue are warranted.

Our results also indicate that it is important for health professionals to acknowledge and address the impact of fatigue on patients with sHTADs. The unpredictability of sHTAD related fatigue is dominant and pervasive, and is experienced as a vicious circle. Helping people to be able to understand and accept fatigue may be important to enable patients to manage and live with fatigue. Support from health professionals to manage fatigue and develop strategies to increase physical activity and maintain work is important for these patient groups.

Our review has shown that the use of many different fatigue measures and cut-off values, make comparisons across studies difficult. To overcome these challenges, our proposal is that multiple stakeholders like researchers, health professionals and patient organizations can cooperate to create standardized sets of outcomes relevant for the sHTADs. This will enable agreement on what aspects that are important to measure, how it should be measured and how results should be interpreted. International collaboration project for sHTADs may also be appropriate, including outcome measures for fatigue.

Limitations and strengths

Only literature written in English, German, French and the Nordic languages were included in the systematic review, this might be a limitation. However, no studies written in other languages with English abstract were found. Our choice of search words and our cultural conceptual understanding may have limited our identification of papers and our interpretation of the content from the identified studies. We excluded case reports and studies with less than six participants. A strength may be the use of predefined criteria for critically appraising the literature, blinded by two reviewers and independently selected and categorized the studies, with the supervision of one other.

There are several limitations related to the focus group interviews. The retrospective perspective may imply possibility for recall bias. Our findings may also be limited to the patients with sHTADs who were willing to talk about their experiences and challenges. Another limitation may be how the term fatigue and exhaustion were interpreted by the participants. They may have different understanding of these concepts, but one of our intentions was also to examine the differences in perceptions and experiences about the concept of fatigue. Both the moderators and the co-moderators were experienced clinicians and/or researchers, and they underlined the interest in all types of narratives. In the analysis we carefully tried to identify and exclude repetitive patterns concerning our expectation and pre-understandings, as recommended in the literature [48, 50]. To ensure the transparency of the study, anonymized data are available on request to the authors (TRS, National resource Center).

Conclusions

This is the first systematic review and qualitative study of fatigue in sHTADs. Our study indicate that fatigue is an under-recognized and under-researched feature in patients with sHTADs. A total of 33 articles were found, including several types of study designs. The majority dealt with MFS, and very few studies addressed other sHTADs. The studies were limited by small study sizes, low response rates, inadequate description of inclusion criteria and the patients’ diagnoses, and incomplete descriptions of the analyses. Despite these limitations, all studies indicated that the prevalence of severe fatigue in sHTADs is much higher than for the general population. The nature and impact of fatigue seems not to be experienced differently between the patients in the various sHTADs. Both the results from the included articles and the focus groups indicated that fatigue seems to have remarkable negative impact on daily life and quality of life. Fatigue may also be a major reason for early retirement. This suggests that fatigue should be considered as a core symptom and outcome measure in clinical trials and clinical practice for all patients with sHTADs. As most patients with sHTADs will not be cured in their lifetime, identifying causes of fatigue and developing appropriate treatment programs is warranted. Therefore, more research on fatigue in the different sHTADs are crucial.