Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) encompasses diverse symptoms that manifest variably across a range of body systems, the characteristic symptoms being chronic unexplained fatigue (lasting more than 6 months) and post-exertional malaise (PEM)—a disabling and exacerbated disease state following bouts of physical or mental exertion that exceed a patient-specific threshold. ME/CFS also entails a varied kaleidoscope of other symptoms including muscle weakness, migraine, flu-like symptoms, cognitive impairment (“brain fog”), and sensitivities to a variety of external stimuli that may include light, sound, or specific odors. This can be accompanied by comorbidities, such as fibromyalgia, postural orthostatic tachycardia (POTS), and Ehlers–Danlos syndrome.
A major challenge for this field of study has been the varied usage of multiple diagnostic case criteria that may render comparison between studies difficult depending on the composition of the participant cohort. Furthermore, these criteria are slow processes of exclusion that leave patients without the support or acknowledgment that they need for extended periods and they may be subjected to a protracted, harsh, and insensitive diagnostic gauntlet. These problems are further compounded by medical guidelines in some developed countries that are out of date regarding ME/CFS clinical practice and require urgent overdue revision.
Case definitions, such as the commonly termed Oxford [1
] or Fukuda [2
] criteria, are most often utilized throughout the UK and USA, respectively, yet may fail to discriminate between generalized chronic fatigue and ME/CFS which specifically also involves PEM, which aids in characterizing this disorder as a discrete clinical entity. Also in usage are the Canadian Consensus Criteria [3
] and International Consensus Criteria [4
], which mandate PEM for a diagnosis of ME/CFS and therefore may be considered more specific definitions. While the presence of PEM is an optional component of the Fukuda criteria, PEM is, unfortunately, not required for research participation by all studies using this or other less strict definitions. Consequently, the discovery of a reliable diagnostic biomarker is perhaps the most common recurring theme in modern ME/CFS research. Despite myriad relevant study outcomes [5
], no such discovery has yet been widely validated or implemented as a suitable diagnostic biomarker of ME/CFS.
Not only does ME/CFS affect multiple body systems and organs, but it does so with different and time-varying levels of severity and different patterns of comorbidities in different individuals, thereby producing a highly heterogeneous patient population [7
]. This complexity represents a major challenge to the task of incriminating one underlying pathological mechanism. It is also possible that different causative molecular insults result in different subsequent clinical presentations and this could contribute towards heterogeneity in the disorder. Patient subtyping to manage this heterogeneity has been previously discussed in the field [20
] and is lent credence by reproduced patterns of differential disease-associated gene expression [24
], gene expression profiles concurrent with comorbid POTS [27
], distinct DNA methylation profiles associated with quality of life scores and PEM [28
], severity and frequency of physical or mental fatigue [29
], or irritable bowel syndrome (IBS) comorbidity [30
], which can be concurrent with specific changes to patient metabolism [31
]. As timely, objective, and accurate diagnosis remains the most clear challenge facing the field, patient subtyping may be an important component of new diagnostic techniques and has seen early investigation with stratification-based severity scores [32
] or cytokine co-expression patterns [33
In summation, ME/CFS etiology has been difficult to pin down due to the combination of a diagnostic quagmire and the disorder’s heterogeneous symptom presentation across multiple body systems. A traditional view has held that ME/CFS onset is often precipitated by some manner of bodily insult, commonly infection, however, the disorder is left without any known single causative pathogen to date. Given the heterogeneity of the patient population, this is unsurprising. It is possible that the initial pathological insult may not always be pathogen-mediated and could instead be instigated by alternative stresses of sufficient magnitude as to nudge homeostatic regulation loops into alternative stable states [34
], and these varying modes of initial insult may contribute to the heterogeneity of ME/CFS clinical presentation.
Current research shows a tangible biomedical foundation underlying this clinical puzzle. Most of this evidence pertains to disturbed muscle function, metabolism, mitochondria, immunity, signaling, neurological, adrenal, and gut health. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift influencing each of these systems, perhaps differentially between individuals with varying clinical features. Furthermore, evidence of abnormalities affecting multiple systems is based on associations and the causal mechanisms responsible for the underlying pathology have yet to be determined. The following sections will address the current evidence for dysfunction across these systems in ME/CFS with specific examples of potential pathological interactions.
ME/CFS is a heterogeneous condition that may encompass scenarios where uncertain, and possibly varying, underlying insults trigger body-wide molecular and cellular perturbations perpetuated by an alternative stable homeostatic states. Diagnostic advancement and the development of tools which objectively and accurately phenotype patients is therefore paramount for the development of mechanistic insight and effective therapeutics.
It is likely that the inflammation and immune dysfunction classically studied in ME/CFS are entangled with dysfunctional energetics, gut health, or autonomic and adrenal dysregulation. The evidence for metabolic and mitochondrial dysfunction indicates inefficient respiration, impaired provision of TCA cycle substrate, and metabolic shifts towards the utilization of alternative metabolites. Immune effector cell dysfunction, chronic inflammation, defective signaling, and elevated oxidative stress may interact with not only the dysfunctional energetics but also with abnormal gut physiology and microbiota composition. These effects on the gut may also tie back to mitochondrial function and vice versa. The reciprocal interactions between these affected systems and the varied clinical presentation of relevant symptoms between individuals make it difficult to postulate cause–effect relationships with confidence. Furthermore, while disturbances to this range of interconnected systems across the body have been demonstrated, in some cases concurrently, this body of research has historically relied upon correlations, which creates the urgent need for research utilizing direct experimental investigation of cause–effect relationships.