Are there subgroups of chronic fatigue syndrome? An exploratory cluster analysis of biological markers

Chronic Fatigue (CF) affects a substantial proportion of the population. In adolescents, about 20% of girls and 6.5% of boys report to have been severely fatigued during the last month [1, 2]. The label Chronic Fatigue Syndrome (CFS), sometimes referred to as Myalgic Encephalomyelitis (ME), may be appropriate if the fatigue is unexplained, long lasting, disabling and accompanied by other symptoms such as post exertional malaise, musculoskeletal pain, orthostatic intolerance, and cognitive problems [3]. Adolescent CFS prevalence is estimated at 0.1 to 1.0% [4‐6], and CFS may have detrimental effects on psychosocial and academic development [7, 8], as well as family functioning [8].

The diagnostic criteria of CFS has been a scientific controversy for decades. As no diagnostic biomarker has been discovered, the diagnosis depends upon specific constellation of symptoms. One part of the scientific community has promoted wide diagnostic criteria [9‐11], and also maintained that CFS is most properly understood as a variant belonging to an even broader category, such as Functional Somatic Syndrome [12] or Bodily Distress Syndrome [13]. This “lumping together” tendency has been strongly opposed by another part of the scientific community, advocating CFS as a heterogeneous group of patients with different diseases and pathophysiological features, e.g., ME is claimed as a distinct unique entity different from other fatiguing conditions, such as reflected in the Canadian diagnostic criteria of CFS (sometimes referred to as the International Consensus Criteria of ME/CFS) [14, 15]. The commonly used Fukuda-criteria [16] as well as the more recently proposed SEID-criteria [3] may be taken to represent pragmatic compromises.

Nevertheless, the net result has been a confusing existence of at least 20 case definitions. Most of them require between 3 and 6 months of unexplained fatigue but vary considerably regarding requirement of additional symptoms. In a systematic review from 2014, Brurberg et al. could not draw firm conclusions concerning the validity of any of these criteria due to weak methodology and inconsistent results of the 38 included validation studies [17]. Accordingly, studies from our own institution question the validity of the Canadian-criteria [18] as well as the SEID-criteria [19] for diagnosing CFS in adolescents.

In an attempt of investigating possible subgroups within widely defined CFS cohorts, latent class analyses have been applied; recent reports suggest the presence of discrete endophenotypes [20‐23]. However, these approaches still rely on subjective reporting of symptoms, and it remains unclear to what extent a specific endophenotype corresponds with certain pathophysiological mechanisms or etiological factors. The presence or not of such correspondence may be considered essential for a proper understanding of the underlying disease mechanisms of CFS.

Despite the absence of diagnostic biomarkers, associations between CFS and candidate genetic markers as well as certain aberrations of immunological, autonomic, neuroendocrine, cognitive and sensory processing functions have been firmly established in previous research [24]. As for genetic markers, a single nucleotide polymorphisms (SNP) in the gene encoding the catecholaminergic breakdown enzyme COMT (catechol-O-methyltransferase) has been linked to CFS in several reports [25, 26]. In addition, mutations in the serotoninergic system are one of the most consistently reported findings in genetic studies of CFS [27‐29]. As for immunological aberration, the most consistent finding appears to be a tendency towards low-grade systemic inflammation, as reflected in elevated serum C-reactive protein (CRP) [30], elevated pro-inflammatory cytokines [31, 32], and increased levels of innate immunity gene products in whole blood gene expression analyses [33]. Also, low-grade inflammation has been hypothesized as a common pathophysiological phenomenon across fatigue states in general [34]. As for autonomic aberrations, most studies suggest a sympathetic predominance, reflected in increased sympathetic cardiovascular activity [35‐38], decreased parasympathetic (vagal) heart rate control [39], altered sympathetic thermoregulatory responses [39], and increased plasma and urine catecholamines [30, 40]. This sympathetic predominance may be the underlying cause of the Postural Orthostatic Intolerance Syndrome (POTS) phenomenon, which is frequently observed among CFS patients [3]. As for neuroendocrine aberrations, attenuated hypothalamus–pituitary–adrenal [HPA] axis dynamics is a consistent finding across adult and adolescent CFS studies [30, 41‐44]. Interestingly, normalization of HPA responses may be associated with improvement of symptoms and functional disabilities [43, 45]. As for cognitive functions, previous research has provided evidence of aberrations in the domains of attention, memory and reaction time [46‐48]. Studies specifically addressing executive functions in adolescent CFS patients have reported impaired interference control [49, 50], cognitive flexibility [51], and working memory [50, 52]. Finally, as for sensory processing functions, three studies have reported strongly reduced pressure pain thresholds [53‐55], suggestive of central sensitization to afferent sensory stimuli [56]. Accordingly, functional brain imaging studies have demonstrated differences across CFS patients and healthy controls [57].

Thus, an alternative approach for delineating possible CFS subgroups would be to use the above-mentioned biological aberrations as a point of departure instead of subjective symptoms when performing subgroup-generating statistical analyses. To the best of our knowledge, such an approach is novel in the field of CFS. In the present study, we aimed to: a) Explore possible subgroups based on biological aberrations within a widely defined cohort of adolescent CFS patients; b) Investigate to what extent these subgroups are associated with constitutional factors (including genetic markers), diagnostic criteria, subjective symptoms and prognosis.

Of the 120 CFS/ME patients included in the NorCAPITAL project, four were excluded from further analyses due to lack of valid data, leaving 116 for analyses in the present study. In this group, 28% were males, and mean age was 15.4 years (Table 1).

Separate cluster analyses within each domain of variables revealed substantial cluster overlap as well as few statistically significant associations with symptoms, functional abilities and prognosis. However, from each analysis it was possible to identify the most important variables driving the cluster formation, which in turn were carried over to the final cluster analysis across all domains (Additional file 2).

The final cluster solution revealed six clusters based on a total of 10 variables (Fig. 2, Table 2). Cluster 1 is characterized by high pressure pain threshold levels and high scores on cognitive function tests, and was labelled pain tolerant & good cognitions. Cluster 2 is characterized by high urine cortisol:creatinin ratio, which signalizes restored HPA dynamics. Cluster 3 is characterized by a strong tachycardia response and corresponding fall in stroke volume during orthostatic challenge, typical of orthostatic intolerance. Cluster 4 is characterized by high levels of interferon gamma (INFγ) and interferon gamma-induced protein 10 (IP-10), indicative of low-grade inflammation. Cluster 5 is characterized by low pressure pain threshold levels and low scores on cognitive function tests; this “mirror image” of cluster one is labelled pain intolerant & poor cognitions. Cluster 6 is characterized by strong power of heart rate variability within the high-frequency (HF) domain, reflecting high vagal (parasympathetic) activity. Few individuals (a total of 4 and 3, respectively) belonged to cluster 4 and cluster 6.

There were no significant differences between clusters regarding demographic and constitutional variables, including candidate genetic markers (Table 3). However, individuals belonging to Cluster 5—Pain intolerant & poor cognitions—were significantly more prone to adhere to the Canada 2003 diagnostic criteria for CFS. Also, this cluster had significantly poorer scores on the FDI and PedsQL functional inventories as compared to clusters 1–3 (Table 4). Symptoms scores for fatigue (CFQ), post-exertional malaise and depressive thoughts (MFQ) did not differ significantly across clusters. As for changes in symptoms and function over a 30-week follow-up period, there were no significant differences between the clusters, but a non-significant tendency for stronger functional improvement among Cluster 5—Pain intolerant & poor cognitions (Table 5).

A scatterplot of the three most important variables for the final cluster formation (urine cortisol:creatinine ratio, Δ HR orthostatic response and digit span forward) revealed a substantial overlap between the clusters (Fig. 3).

The most important finding of the present study is that within a widely defined cohort of adolescent CFS patients, clusters corresponding to certain pathophysiological characteristics could be delineated, but overlap between clusters were substantial and no distinct subgroups could be identified. Also, there were scarce associations between clusters and constitutional factors, subjective symptoms and prognosis.

Medical diagnoses remain the foundations for treatment, rehabilitation, and prognostic assumptions; hence, the importance of valid diagnostic entities can hardly be underestimated. Sadly, the lack of objective criteria for CFS has contributed to the co-existence of multiple sets of diagnostic criteria, all of which are based on subjective reporting of symptoms. It is frequently maintained that certain case definitions correspond to specific underlying disease mechanisms; for instance, the Canada 2003 definition put strong emphasis on a possible inflammatory pathophysiology [14]. Accordingly, it is often argued that studies based on a wide diagnostic definition of CFS (i.e., a definition that requires a minimum of accompanying symptoms), such as the Oxford criteria [11], are at risk of introducing substantial heterogeneity in the patient sample which in turn may obscure results that pertain to a specific subgroup only. Specifically, it is frequently maintained that the use of a wide diagnostic definition in clinical trials tend to select a large portion of patients suffering from mental distress who may benefit from psychological/behavioural interventions, whereas such interventions are claimed to be unhelpful (or even harmful) for the potential subgroup of patients suffering from another (such as inflammatory) disease mechanism [75].

This argument seems to rely upon an a priori-assumption of the existence of subgroups within a widely defined CFS cohort, and the related research efforts tend to focus on how such subgroups can be found from analysis of patients’ symptoms (or biomarkers yet to be discovered). However, a more fundamental scientific question, which has scarcely been addressed in previous research, is whether such subgroups exist at all. In the present study, while the cluster analyses did suggest some delineation corresponding to previously identified characteristics of CFS pathophysiology, such as low-grad inflammation, altered HPA dynamics, and orthostatic intolerance, the most striking finding is the absence of well-defined subgroups. Rather, the data seems to represent continuous variables in a multidimensional space. Accordingly, the clusters were not significantly associated with symptom scores nor prognosis. Taken together, the findings of the present paper favor a “lumping together” rather than “splitting apart” approach to CFS caseness, and question the clinical usefulness of searching for CFS subgroups as well as the validity of the most “narrow” CFS diagnostic criteria. If confirmed by future research, this finding may have important clinical implications. It would suggest, for instance, that well-documented rehabilitation strategies might be applicable to a wide range of CFS sufferers.

That said, the cluster analysis did reveal some interesting associations, such as the positive association between restored HPA axis and functional abilities, confirming findings from previous reports [43, 45]. Also, there was an association between low pain tolerance and cognitive functions, poor functional abilities and quality of life, and adherence to the Canada 2003 diagnostic definition of CFS [14]. The causality of these associations remains to be clarified; for instance, functional disability may have a negative impact on cognitive test performance, as well as the other way round. Anyway, a better characterization of this particularly vulnerable group of CFS patients may help to tailor clinical rehabilitation programs.

Interestingly, while low-grade inflammation is advocated as an important pathophysiological feature of CFS patients adhering to the Canada 2003 diagnostic criteria [14], results from the present study opposes these assumptions. The cluster characterized by low-grade inflammation was not associated with the Canada 2003 case definition for CFS, while the cluster characterized as Pain intolerant & poor cognitions, which actually was associated with the Canada 2003 case definition, had the lowest score on inflammation variables. This result corroborates previous finding from our group [18], and further questions the validity of the Canada 2003 case definition.

Within a widely defined cohort of adolescent CFS patients, clusters could be delineated based on biological markers, but no distinct subgroups could be identified. Associations between clusters and constitutional factors, subjective symptoms and prognosis were scarce. These results question the clinical usefulness of searching for CFS subgroups, as well as the validity of the most “narrow” CFS diagnostic criteria.