Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available. Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease’s multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances. This comprehensive model not only advances our understanding of ME/CFS’s pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease’s complexity and the multifaceted approach required for its study and management.

Introduction

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) (1–3) (hereafter referred to as ME/CFS) is a debilitating chronic multisystem illness. ME/CFS is estimated to have a global prevalence ranging from 0.1-0.8% (4–7). It is thought to affect some 17 to 24 million people worldwide (8) and the United States (U.S.) Centres for Disease Control and Prevention (CDC) and the U.S. National Academy of Medicine estimate that there are approximately 836,000 to 2.5 million (2, 9) individuals diagnosed with ME/CFS in the U.S., with a quarter of these patients thought to be housebound or bedbound (10). Additionally, current data from the United Kingdom (U.K.) Biobank has indicated that there are more than 250,000 individuals suffering from ME/CFS in England and Wales (11), with a prevalence of 0.2% in three regions of England (6).

ME/CFS impacts all ages, races, and socioeconomic groups (4, 12). Most patients tend to be diagnosed around middle age (13), but diagnosis has been made in individuals as young as three years old and as old as 77 years (2, 12). Black and Hispanic populations appear to have a higher prevalence of ME/CFS with worse severity than other racial groups (9, 14). Women are affected 2-3 times more frequently than men (2, 4, 8, 11, 12).

Due to the disabling symptoms which include cognitive and physical impairment worsened by exertion (15–17), there is a significant economic burden created by ME/CFS (4) as many patients are unemployed and less than a fifth work full-time (11). It is thought that up to 75% of ME/CFS patients are unable to work (10). ME/CFS is thought to cost the U.S. between $18 and $24 billion annually (18), and £3.3 billion annually in the U.K (19).

In this review paper, we will focus on describing ME/CFS in terms of symptoms, severity and burden, diagnostic criteria, causes and triggers; followed by an overview of the complex pathophysiology and management of the condition. We will conclude by listing research priorities for the future. See Figure 1 for a content overview.

Figure 1

ME/CFS symptoms

ME/CFS is a heterogeneous disease (16, 20), meaning that patients display varying symptoms and several body systems are impacted (11). Although many of the symptoms of ME/CFS overlap with other diseases, one feature that sets ME/CFS apart is a worsening of symptoms in response to relatively minor physical, cognitive, orthostatic or even emotional exertion (13). This phenomenon is known as post-exertional malaise (PEM) or PESE (post exertional symptom exacerbation). Following exertion, patients experience reduced mental and physical stamina, accompanied by accelerated muscle and cognitive fatigue (15–17). PEM is characterised by a delayed onset, prolonged duration, and an intensity disproportionate to the precipitating exertion (15, 16). Fatigue is a prominent feature in most patients; in contrast to physiological tiredness, fatigue is not alleviated regardless of how much patients sleep or rest (2, 21). Common symptoms of ME/CFS are summarised in Figure 2.

Figure 2

12, 15, 22–26). PoTS, postural orthostatic tachycardia syndrome. Created with Biorender.com.

ME/CFS severity classifications

The long-term outlook for ME/CFS patients varies significantly (11). An important prognostic factor is how the illness is managed in its initial stages (27). The chance of full recovery has been estimated to be only 5% (28) as most patients do not regain their full pre-ME/CFS function; a third of patients deteriorate to being house or bedbound (8). Hence, ME/CFS significantly reduces a patient’s quality of life (11, 24, 29–31), impacting activities of daily living, socialising, family life, emotional wellbeing, work, and education (11, 23). Numerous researchers have found that individuals suffering from ME/CFS have a lower quality of life than people with other chronic illnesses, including multiple sclerosis (MS) (32), lung disease (33), rheumatoid arthritis (RA) (33–35), and some forms of cancer (11, 33, 35). Similar to other disabling chronic illnesses, resultant depression and anxiety in ME/CFS are frequent (36) and there is a higher risk of suicide in ME/CFS (37).

Patients’ symptoms can usually be categorised into four levels of severity; mild, moderate, severe, and very severe (11, 29, 38). In mild severity ME/CFS, an individual is still able to attend work or education and perform light tasks (11). However, they are likely to experience difficulties with mobility, and their social life is impacted. In moderate ME/CFS, individuals experience impaired mobility, meaning they are likely unable to attend work or education, cannot undertake activities alone, have decreased sleep quality, and need frequent rest. People with severe ME/CFS are usually housebound (11) and have a functional capacity ranging from 5% to 15% of normal functioning (39). They also experience cognitive difficulties and are hypersensitive to external stimuli (11). Lastly, people with very severe ME/CFS are bedbound (11) and have a functional capacity of less than 5% (39). These individuals are usually completely dependent on others for care, require tube feeding, are unable to complete personal hygiene, and are highly sensitive to sensory stimuli (11). ME/CFS has been described as a fluctuating condition as symptoms change in nature and severity sporadically (40). 61% of patients have reported being bedbound on their worst days (41) and at least one-quarter of ME/CFS patients have recounted being housebound or bedbound at some point in their lives (2). Hence, patients must adapt to life with regular flare-ups and relapses (11, 42).

In one survey of 1418 ME/CFS patients (43), it was found that 98.5% (n=1397) of the ME/CFS participants struggled with performing daily tasks and more than half (n=775) were completely unable to complete their usual activities. Additionally, 93.9% (n=1331) of participants experienced moderate (n=976) or extreme (n=355) pain, 88.6% (n=1256) of patients had trouble with mobility, and 67.3% (n=954) experienced trouble with washing or dressing themselves. However, the severity of ME/CFS means that family members or caretakers are also severely impacted. Of 1418 respondent caretakers/family members, 96.1% (n=1362) felt worried in relation to their family member’s ME/CFS, 84.7% (n=1201) found it difficult to care for their family members suffering from ME/CFS, and 91.8% (n=1302) reported that their family activities were affected. Additionally, caring for a member with ME/CFS negatively impacts sleep, work, holidays, finances, and sex life (43).

Diagnostic criteria for ME/CFS

The original neurological classification of ME/CFS

In 1969, the World Health Organisation (WHO) classified ME/CFS as a neurological disease (44) based on the neurological features of the disease. Positron emission tomography (PET) brain imaging of ME/CFS patients also displays neuroinflammation (45–47). Additionally, abnormalities of the white (23, 48–50) and grey (23) matter have been noted. This neuroinflammation is likely to correlate with cognitive impairments such as lowered information processing speed, decreased reaction time, slower working memory, and reduced attention (51).

Available diagnostic criteria

Despite its high prevalence, there are still no universally accepted clinical criteria to characterise ME/CFS, making early and accurate diagnosis difficult (52). Different ME/CFS diagnostic criteria exist, as described in Figure 3. Additionally, many adult ME/CFS patients make use of the self-scoring Bell Chronic fatigue immune dysfunction syndrome (CFIDS) disability scale, a symptom scale created by Dr David Bell in 1995 (55). However, this classification is subjective, and scores may change due to the fluctuating nature of the disease; they may also vary depending on the physician doing the scoring. Another problem is that a patient may experience one score in one region, but a differing score in another region, making it difficult for the physician to make an overall decision. Despite the large number of criteria for the diagnosis of ME/CFS, it is still unclear which one is the most useful and validated. Current diagnostics rely on medical history, physical examination, and clinical observations, which often require many trips to the doctor and can be exhausting for a patient (11, 23, 56).

Figure 3

1, 2, 11, 15, 16, 22, 52–54). Created with Biorender.com. GET, graded exercise therapy; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; PEM, post-exertional malaise.

Additionally, PEM which can vary from very minimal to extremely severe (e.g. affecting speaking, thinking, eating and drinking, and orthostatic tolerance) is considered a key diagnostic feature of ME/CFS; this is paradoxical as severe and very severe patients are incapable of even the slightest exertion (39). Moreover, diagnosis relies heavily on symptom-based exclusion of other disorders (2, 11, 15, 16, 22, 56, 57), since ME/CFS symptoms overlap with many other medical conditions (23). In essence, since ME/CFS can be a “diagnosis of last resort” (1, 26), it can take years for individuals to receive a diagnosis (22). This prolonged diagnostic process is compounded by differences in exclusion criteria across various definitions of ME/CFS, as highlighted by Jason et al., 2012 (54). Hence, re-evaluation of these diagnostic criteria is essential (57).

Probable predisposition and causes of ME/CFS

The diverse symptom presentation and patient heterogeneity indicate that ME/CFS is likely to have a multifactorial origin (23, 30, 53, 58), with multiple physiological processes implicated in the pathogenesis (52, 59). It is unlikely that one single protein or RNA transcript will be consistent across the disease spectrum (60). It has been proposed that stressful or traumatic incidents in genetically susceptible individuals may trigger the development of ME/CFS symptoms (58, 61). These stressors can include acute infections (61), emotional stress (62), and major life events (61). However, other stressors such as a quick walk, a glass of wine, or a temperature change have also been known to trigger relapses in ME/CFS (63). The next paragraphs will discuss genetic predisposition and susceptibility as an underlying risk factor for ME/CFS - the superimposition of external stressors and exposures (59) results in a state of “aberrant homeostasis”, where a temporary homeostatic state of functioning occurs, but functions at a less optimum level (64).

Genetic predisposition

Unfortunately, there is little consensus among researchers on the genetic, cellular, and molecular influences that alter the risk of developing ME/CFS (21). However, it is thought that ME/CFS may have a genetic predisposition (26, 29, 56, 61, 65–68) as members of the same family have frequently been diagnosed with ME/CFS (65, 67, 68), though they will also tend to share similar lifestyles and cultures. Similarly, genealogic analyses and twin studies have shown a genetic link between ME/CFS patients and their offspring, ensuing a heightened risk of developing ME/CFS in the offspring (26, 66, 69). As expected (70), these diagnoses do not seem to follow predictable Mendelian patterns, suggesting that there are multiple genes and alleles that increase the risk of developing ME/CFS (56). Various studies have found that some ME/CFS patients identified by the Fukuda criteria have a significant excess relatedness for close (first or second degree) and distant (third degree) relatives (66, 68). A large review (56) noted that three studies estimated the narrow-sense heritability (h²) in large cohorts, and two of these studies reported non-zero results, suggesting a heritability risk for ME/CFS. However, other studies have shown no evidence of heritability. One analysis of the U.S. health insurance resulted in a high narrow-sense heritability (h^{2 =} 0.48) (71), while an analysis of U.K. Biobank self-reported ME/CFS patients approximated the h² to be 0.08 with a low confidence (72). Furthermore, another large twin-based study produced inconclusive results (73).

Some polymorphisms in genes related to the immunomodulatory response have been identified (69, 74), such as an increase of TNF-857 TT and CT genotypes (p=0.002), and a significant decrease of IFN gamma low producers (A/A) (P=0.04) in ME/CFS patients in respect to controls (74). Polymorphisms impacting hormone action have also been noted (69, 75). For example, NR3C1-1F DNA methylation was found reduced in patients with ME/CFS and coincides with the hypothalamic pituitary-adrenal (HPA) axis hypofunction hypothesis (75). The metabolic kynurenic pathways is likely also implicated in ME/CFS, owing to common mutations in IDO2 (76) such as R248W and Y359STOP (77). However, these genetic associations are inconsistent as studies typically have quality-control issues (56). Additionally, the Gln27 mutation (a polymorphism in the B2dR genes) has been associated with adolescent ME/CFS (78). Such Gln27 mutations, along with Arg16 mutations in adults, can result in an unfavourable cardiovascular profile (79–81). On the other hand, genome-wide association studies (GWAS) studies performed on ME/CFS patient samples from the U.K. Biobank have found no DNA variant repeated in the multiple analyses (82). However, it is not entirely certain how many of these patients met ME/CFS criteria, suggesting that replication studies should be done in future to help us understand the genes, cellular processes, and tissues or cells that causally change the risk for developing ME/CFS. Additionally, pinpointing genetic risk factors for ME/CFS will help combat the disbelief some health professionals have towards ME/CFS (56).

There are also genetic predispositions that render certain individuals susceptible to developing autoimmune diseases (83) and even after Epstein-Barr virus (EBV) infection (30, 84), such as human leukocyte antigen (HLA) variants (30, 84, 85) that have experienced selective pressures whilst co-evolving with pathogens (86, 87). HLA proteins are crucial for the immune system as they distinguish foreign pathogens from self-cells (56). An increased frequency of HLA-DQA1 alleles and reduced expression of HLA-DRB1 was found associated with ME/CFS (88). Additionally, in patients diagnosed with the CCC, the HLA types HLA-C*07:04 or HLA-DQB1*03:03 were shown to be significantly linked to ME/CFS status when using the CCC (89). Since 10% of ME/CFS patients have these alleles, their risk is altered around 1.5-2.0-fold, meaning genetic differences in the immune system may change the risk of developing ME/CFS (89). Some haplotypes also appear to be less resistant to EBV infection, such as DR2-DQ6, DR3-DQ2, and DR4-DQ8, making them more likely to develop EBV-related disorders (90). Although, few researchers think that mitochondrial DNA variants can explain the prevalence of ME/CFS (91–93).

Viral triggers and reactivation

As in other chronic diseases, ME/CFS involves an asymptomatic predisposition stage, then a prodromal stage, followed by symptomatic disease (59). Infection (30, 61, 94–97) is often reported to be a common trigger for the development of ME/CFS, as many patients recognise that the onset of their symptoms coincided with an infectious episode (2, 58, 98). This is recounted by more than 80% of patients (98) and it has been estimated that two-thirds of ME/CFS cases arise following viral infection (85, 99). This is supported by the fact that several ME/CFS outbreaks have occurred in the same geographical region simultaneously (12). Clustering provides strong support for the involvement of infectious agents, as with some cases of MS that ‘appeared’ (100) in the Faroe Islands during World War II upon the arrival of foreign army corps, and was eventually shown to be due to EBV (101). Additionally, many ME/CFS patients experience symptoms similar to bacterial or viral infections which may correlate to specific regions. Infectious pathogens thought to promote the development of ME/CFS are summarised in Figure 4.

Figure 4

2, 25, 29, 85, 102–126). Created with Biorender.com.

It is thought that many chronic illnesses, including ME/CFS, originate with reactivation of latent or dormant viruses that are present in the body, caused by a change in physiological conditions (127). During acute illness, direct consequences of viral reactivation or infection are thought to occur in localised areas such as the brain and neuronal cells, muscle cells, and cardiac myocytes [Extended Figure 8 in (127)]. Since these tissues are rich in mitochondria, it can result in neuronal and autonomic nervous system abnormalities, as well as immune modulation. However, with chronic illness, indirect consequences of viral reactivation or infection are proposed to occur. This occurs in peripheral circulation and can promote symptoms such as postural orthostatic tachycardia syndrome (PoTS), PEM, fatigue, endothelial cell dysfunction, platelet hyperactivation, mast cell activation, and connective tissue disorders. In this chronic phase, it is thought that auto recovery is difficult (127).

Viral pathogens that often persist in a dormant manner include herpesviruses such as the extensively studied EBV (52, 94, 95, 113). Reactivation of herpesvirus has interestingly been hypothesised as a key mechanism in the development of ME/CFS (128). In support of this theory, one paper investigated the possibility of EBV-encoded proteins existing in ME/CFS, such as BRRF1 and BLLF3, and the effects they may have (52). BRRF1 plays a role in the switch between latent and lytic EBV replication (129), while BLLF3 encodes a dUTPase and is expressed in the early phase of EBV lytic replication (52). Similarly, evidence for antibodies against HSV-1 (127), EBV (127, 130, 131), and HHV-6 (130) dUTPase proteins has been identified in ME/CFS. These dUTPase proteins, along with other viral dUTPases such as HSV-1 and HHV-6, are thought to promote cellular damage and promote autoimmune features, as well as promoting mitochondrial fusion and decreasing energy production (127). This antibody presence is thought to potentially elevate cytokine and chemokine levels, which is dependent on toll-like receptor (TLR)-2 signalling and causes NF-κB activation (132, 133). Hence, the EBV UTPase may act as a novel pathogen-associated molecular pattern (PAMP) ligand protein for TLR2 (132).

Although EBV proteins may play a role in the progression of ME/CFS (52), researchers have hypothesised that the virus has a third state termed the abortive/leaky/lytic replication, as has been suggested upon analysis of the EBV genome in T and NK cells of patients with chronic EBV infection (134–136). The presence of EBV dUTPases may cause neurological abnormalities in ME/CFS via changes in gene expression, resulting in modulated neurological circuits (137). Moreover, EBV dUTPases could also induce immune dysfunction (52).

However, earlier serological studies on EBV and ME/CFS using classical EBV antigens have resulted in contradicting results that illustrate no upregulation of EBV-encoded proteins (99, 138–147). More advanced studies using peptide microarray (148) and suspension multiplex immunoassay (149) have also not found a significantly higher EBV anti-immunoglobulin (Ig)-G response in ME/CFS patients in comparison to controls. Most studies have not reported a significant increase in the viral load in ME/CFS patients in comparison to controls. Due to this evidence, some researchers believe that herpesviruses as one of the causes of ME/CFS is a “fading” hypothesis (150). However, a trigger does not have to linger. Equally, heterogeneity in patient groups, the absence of uniformity in case definitions, and differences in reliability and precision could have resulted in there being no correlation between the viral load and serological data (61, 99, 103, 109).

That said, serological data are probably of limited use as an indicator of EBV reactivation (151). Although there is substantial evidence that ME/CFS has a viral trigger (94, 95), symptom severity and burden are often not related to the severity of the triggering viral infection and its symptomatology. Additionally, there are alternative theories differing to a post-viral causation, as noted later in the text.

Toxin and drug exposure

Some also hypothesise that toxin exposure could trigger ME/CFS (61), such as organophosphate compounds (152, 153) and heavy metals (154). In the early 1960s, researchers found that workers with chronic exposure to organophosphates, mainly in insecticides and after sheep dipping, experienced persistent central nervous system (CNS) changes (153). This included disabling fatigue exacerbated by exercise and associated with myalgia, excessive sleep, night sweats, irritable bowel syndrome (IBS) symptoms, and mental changes. It was hypothesised that the organophosphates induce various abnormalities such as an elevated prevalence of lymphoproliferative disorders associated with impaired natural killer (NK) cell and cytotoxic T cell function. Additionally, exposure to heavy metals, such as cadmium, may also contribute to the development of ME/CFS (154). Cadmium is a widespread environmental and occupational heavy metal pollutant and can potentially cause neurological symptoms. Cadmium induces neuronal death in cortical neurons through a combination of apoptosis and necrosis, involving reactive oxygen species (ROS) generation and lipid peroxidation (155). This action may explain decreased grey matter volume in ME/CFS (156), as well as certain effects on the CNS such as reduced attention levels and memory (157). Exposure to cadmium also potentially reduces cerebral blood flow (158) [particularly cortical blood flow (159)], as cadmium has a disruptive effect on angiogenesis (160). This reduced blood flow can result in neurological dysfunction and the abnormal neuroimaging observed in ME/CFS (158). Cadmium may accentuate inflammatory processes, which may in turn disrupt the HPA axis and trigger symptoms of ME/CFS (161, 162). However, the exact organ that cadmium toxicity targets is still unclear (154).

Additionally, cases of ME/CFS have also been recorded post-immunization (163) and many patients are fearful that vaccinations will worsen their already dysfunctional immune system and cause symptom exacerbation (164). More recently, ME/CFS development after the Sputnik V COVID-19 vaccination has been recorded (165). Some research about vaccination safety relates to adjuvant compounds used in some vaccinations to promote lasting immunization (166, 167). For example, aluminum hydroxide salts, often used as vaccine adjuvants, have been found to abnormally persist within immune cells at the site of previous immunization, resulting in macrophagic myofasciitis lesions (168). These inflammatory macrophage formations can result in associated microscopic muscle necrosis. While transient aberrant changes associated with aluminum hydroxide salts are acknowledged, the direct link between microscopic muscle necrosis and the mechanisms underlying ME/CFS requires further investigation. However, no indication of an increased risk of developing ME/CFS was found post-HPV vaccination (169). Additionally, ME/CFS patients were found to have similar humoral and cellular immune responses as healthy controls post-influenza vaccination (170) without worsening ME/CFS symptoms or causing adverse effects (164, 171).

Furthermore, various drug exposure has been found to trigger symptoms that are typically present in ME/CFS (172). For example, widely prescribed fluoroquinolone antibiotics are usually prescribed to treat various infections such as pneumonia and sinusitis (173–175). However, these fluoroquinolones have been found to increase tendinopathy involving oxidative stress and mitochondrial toxicity (176–180). Hence, the use of such drugs may have a multisystem effect and lead to the development of chronic illnesses such as ME/CFS.

The complex pathophysiology of ME/CFS

As a consequence of infection and other stressors, such as poly-trauma for example (181), a state of acute inflammation and aberrant immune activation may occur. A compensatory anti-inflammatory mechanism then typically follows (59), causing an imbalance in immune responses (58, 59) combined with hypothesised autoimmunity (30, 52, 85, 182). This may lead to subsequent physiological abnormalities including gut dysbiosis and systemic inflammation, eventually resulting in a pathological clotting system, chronic endothelialitis, vasoconstriction, and hypoxia, as found in similar conditions such as heat stroke (183). Additionally, dysfunctional energy metabolism (52, 184–186) along with oxidative stress (187, 188) are also hypothesised in the development of ME/CFS. It is hypothesised that these mechanisms occur in a spiralling, progressive way, toppling the host’s homeostatic equilibrium (59).

Gut dysbiosis

ME/CFS patients often have gastrointestinal (GI) symptoms (189) with gut inflammation (190), gut microbiome dysbiosis (57, 191) and changes in the gut microbiome (191, 192). A reduction in microbiome diversity has been identified (191), but it is likely that the microbiome composition will differ between ME/CFS patients as each patient has a unique infectious history (193). In ME/CFS, anti-inflammatory bacterial species such as Faecalibacterium (191, 194) and Bifidobacterium (191) are decreased, resulting in a decreased production of anti-inflammatory butyrate (191, 194). Butyrate is essential to maintain the mucosal barrier and immunomodulation (195), whilst having anti-inflammatory effects through downregulating pro-inflammatory cytokines (196). However, this decrease in Faecalibacterium is found in various disorders, and is not specific for ME/CFS (197). Similarly, some studies found an elevation in short chain fatty acids (SCFAs) butyrate, isovalerate, and valerate (198), contradicting these other articles. Conversely, proinflammatory Proteobacteria species have an elevated concentration in ME/CFS (191, 194). Proteobacteria are known as a “microbial signature of disease” (199) and one form, Enterobacteriaceae, is specifically increased in ME/CFS (191). This increased concentration of Enterobacteriaceae may result in increased transit time and IBS-like symptoms (200). It is also not yet known whether such dysbiosis leads to ME/CFS, or whether it is a consequence of the metabolic and immunologic changes that occur in the disease (201).

It is hypothesised that once an acute infection has dysregulated the host’s immune system, pathogens are capable of intracellular persistence where they escape immune surveillance (202). When metabolites and proteins expressed by these pathogens are created, they interfere with host transcription, translation, and DNA repair processes, leaving infected immune cells unable to express human metabolites. Since these pathogen proteins and metabolites are often similarly structured to ones created by the human host, such molecular mimicry makes it difficult for the host to recognise the foreign pathogen (193), resulting in the host’s immune system becoming increasingly sluggish and more susceptible to acquiring other infectious agents. This causes patients to become increasingly dysbiotic as their immune system weakens over time, and successive infections may explain the variability of symptoms experienced in ME/CFS (193).

Microbe-associated molecular patterns (MAMPs) are molecules found on bacterial surfaces (203) which interact with the immune cell receptors of the host to promote inflammation (204). Elevated levels of IgM and IgA antibodies to one potent MAMP- exotoxin lipopolysaccharide (LPS)- have been observed in ME/CFS (205), as well as higher blood levels of bacterial LPS, LPS-binding proteins, and soluble CD14 (191). LPS is a structural component in the outer membrane of many Gram-negative bacteria, and it has various immunostimulatory and procoagulant effects (206). LPS molecules have been identified as potent inflammagens (207–209) having cytotoxic and neurotoxic effects (210–214) and heightening the production of pro-inflammatory cytokines (215–218).

These inflammatory markers also indicate translocation of gut bacteria and toxins from the GI tract into the blood (191), which may result in systemic inflammation in ME/CFS (183). Specific gut inflammation (190) and gut hyper-permeability (219) have been identified, and microbe and virus communities may also persist in ME/CFS blood and brain tissue (193). Not only does the abundance of bacterial taxa correlate with the symptoms of pain and fatigue (191, 194); metabolomic results illustrate an expression of bacterial genes, rather than human (194). In essence, there appears to be a link between the microbiome, gut inflammation, and the symptoms of ME/CFS (201).

Additionally, the diverse intestinal virome that is established from birth (57) includes many prokaryotic viruses called bacteriophages (220). Bacteriophage richness was found elevated in one ME/CFS study, but it is limited owing to its small sample sise (191). Since bacteriophage predator-prey dynamics regulate the diversity and equilibrium of the bacterial microbiome (221), alterations in the virome can also cause intestinal microbial dysbiosis in different diseases (222–224) and alter microbiome homeostasis. Future studies need to include standardised techniques and analyses when doing further research into the virome as it is particularly understudied in ME/CFS (57).

External stressors like stressful or traumatic incidents, acute infection, and toxic stressors may result in widespread and chronic systemic and even neuroinflammation, driven by a variety of inflammatory molecules in circulation. Such molecules might have their direct origins from previous infections and the resulting gut dysbiosis, as summarised in Figure 5.

Figure 5

57, 183, 190–196, 201, 203–209, 215–218). Created with Biorender.com. MAMP, microbe-associated molecular pattern; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Systemic inflammation

Systemic inflammation (225) and neuroinflammation (45–47) are thought to play a major role in ME/CFS. Chronic inflammation is a crucial hallmark of persistent infection (193), as infections can alter proinflammatory and anti-inflammatory cytokine and chemokine expression, adjusting the inflammatory and immune responses (30). Although inflammation is reflected in selective biomarkers, traditional inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate have also shown an increased trend in ME/CFS, particularly in those with mild/moderate disease generally not raised in ME/CFS (226).

Circulating inflammatory molecules

Early ME/CFS has been associated with elevated proinflammatory cytokines (227–230) and a distinct cytokine inflammatory profile (225, 231). Heightened circulating inflammatory cytokines are crucial in driving the development of autoimmune diseases (232). These heightened cytokines are mainly related to Th1 and Th2-driven responses, but not all studies have found consistent results. However, as ME/CFS persists over several years, it is hypothesised that the inflammatory profile (231) and plasma immune signatures change with increasing disease duration (225). Perhaps this indicates that in the early stages of ME/CFS, the immune system actively attempts to target the infectious burden (193); however as the disease progresses, pathogens in the microbiome disable the immune response and “immune exhaustion” occurs (233, 234). In essence, acute pathogens can cause chronic symptoms in ME/CFS by existing in latent forms (193).

Cytokine activation has been noted in ME/CFS patients (225) and appears to increase along with disease severity (231). This suggests that patients with ME/CFS may struggle with an increasing infectious burden over time. One study noted 17 cytokines had a significant upward linear trend with the severity of ME/CFS: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN (interferon)-y, interleukin (IL)-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α (231). Out of these 17 cytokines, 13 are considered proinflammatory cytokines. Although these 17 cytokines are linearly correlated with ME/CFS increasing severity, they did not differ significantly between control and ME/CFS groups. This correlation of cytokine levels with severity may indicate that severity is a useful way to subgroup ME/CFS, as well as a dose-response defect in the metabolism or excretion of cytokines (231). A summary of the interactions between circulating inflammatory molecules can be found in Figure 6.

Figure 6

Redox imbalance and oxidative stress

Inflammation is bidirectionally linked to redox imbalances (248) as inflammation produces ROS and reactive nitrogen species (RNS), whilst redox imbalances cause cellular damage, evoking an inflammatory response (249, 250). Redox imbalances (251, 252), oxidative stress (182, 187, 253–255), nitrosative stress (182), and chronic ischaemia-reperfusion injury (256) have all been found to be central to ME/CFS. Markers of oxidative stress have been found in ME/CFS and, importantly, correlate with symptom severity (251) (Table 1).

Nitrosative stress is also present, as illustrated by markers of nitrosative stress such as increased NOS and NO (182, 297), peroxynitrite (182, 297), elevated NF-κβ production (182), and nitrate after exercise (182, 297). Even though NO is physiologically critical to vasodilation and neurotransmission (251), excess NO and RNS are damaging as they directly attack antioxidant enzymes such as catalase (298), promoting redox imbalance.

When muscle afferents are triggered by muscle fatigue, this triggers the production of heat shock proteins (HSPs) (299). HSPs protect muscle cells against any deleterious effects of ROS generated during exercise by activation of antioxidants (300, 301). In turn, the elevated antioxidant levels elevate the levels of plasma HSPs. However, prolonged activation of muscle afferents by oxidative stress due to low-grade exercise results in reduced HSP production (266). The formation of HSPs in ME/CFS individuals is reduced (302), and the responses of plasma HSP27 and HSP70 are delayed or lowered, while resting levels of plasma HSP70 are also decreased (303). Hence, this impaired HSP production (302) combined with oxidative and nitrosative stress, and low-grade inflammation could explain the exercise intolerance and muscle dysfunction seen in ME/CFS patients (303, 304).

Dysfunction of the vasculature, endothelium, and coagulation

Since persistent inflammation and immune cell activation is present in ME/CFS (305), vascular changes and endothelial damage (306, 307) will coexist due to the interplay between inflammation and vascular alterations. The altered autoregulation of blood flow cannot meet the metabolic demand of tissues in ME/CFS, leading to tissue hypoxia and subsequent ischaemia/reperfusion injury with its associated symptoms and signs (29).

Endothelial damage

Endothelial cells are important regulators of the immune system (308); endothelial dysfunction can promote oxidative stress and inflammation (309). The abnormal immune responses present in ME/CFS are thought to impact endothelial cell function (29) and patients show signs of endothelial dysfunction (306, 310). Endothelial dysfunction has been demonstrated in vivo (306, 311), in the large vessels of ME/CFS patients (307, 311) through flow-mediated dilation (FMD) and in the microcirculation through post-occlusive reactive hyperaemia.

FMD measures the dilation of blood vessels triggered by the release of NO from endothelial cells in response to shear stress (307, 311). It was also found that ME/CFS patients are unable to dilate their vessels adequately by endothelium-independent vasodilation when given sublingual nitroglycerin to promote relaxation of the vessels. Additionally, myocardial infarction associated transcript (MIAT) was found to be upregulated in PBMCs of ME/CFS patients, indicating endothelial dysfunction (312). Additionally, microclot presence (313) in ME/CFS may also cause damage to the endothelium. However, the endothelial damage observed in ME/CFS patients does not appear to correlate with the usual markers of endothelial dysfunction seen in cardiovascular disease such as increased levels of symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA), and high-sensitivity C-reactive protein (hs-CRP), and reduced levels of arginine and homoarginine (311). This may suggest that a different mechanism is at play, which could relate to the abnormal immune response present in ME/CFS (311). Endothelial dysfunction can result in capillary leakage, accelerated inflammation, hypercoagulation, platelet aggregation, and decreased vascular tone (314).

MicroRNAs (miRNAs) are important to maintain endothelial function and altered miRNA profiles are often used to predict, diagnose, and monitor diseases (315). Studies have revealed interesting miRNA changes in ME/CFS. Silent information regulator 1 (Sirt1), an anti-inflammatory and anti-oxidative protein (316), increases the production of NO by activating endothelial NOS (eNOS) in endothelial cells in response to shear stress (317). The NO released by endothelial cells controls the vascular system to ensure sufficient blood and oxygen reaches tissues throughout the body. During inflammation and oxidative stress, eNOS uncoupling or reduction can occur (318), as well as decreased activity or expression of Sirt1 (316). In ME/CFS, a set of plasma miRNAs known to modulate the Sirt1/eNOS axis were analysed, showing elevation in miR-21, miR-34a, miR-92a, miR-126, and miR-200c (305). These five miRNAs have also been found increased in PBMCs from different cohorts. The functions of these miRNAs are illustrated in Figure 7; they relate to endothelial function signalling pathways, including oxygen regulation and oxidative stress. Hence, miRNAs may serve as a potential biomarker in ME/CFS, although they do not correspond with disease severity (305).

Figure 7

Autonomic dysfunction, vasoconstriction, and hypoxia

Many ME/CFS patients have a unique cardiovascular situation (58) and changes indicative of autonomic dysfunction (329–331). One cluster analysis of 131 ME/CFS patients diagnosed according to the Fukuda criteria revealed that 34% of patients experienced sympathetic symptoms with dysautonomia (and were associated with more severe disease severity), 5% from sympathetic symptoms alone, 21% parasympathetic, and 40% struggled with sympathovagal balance (331). However, studies assessing autonomic dysfunction in ME/CFS are equivocal (329). Since heart rate parameters often reflect changes in autonomic function, one meta-analysis analysed 64 studies to assess differences in heart rate parameters in ME/CFS (329). It was concluded that, in comparison with controls, patients with ME/CFS have a higher resting heart rate, lower maximal/peak heart rate, higher heart rate responses to head-up tilt testing and moving from sitting to standing, and a lower heart rate at submaximal exercise threshold. Moreover, the resting heart rate variability (HRV) parameters also differed in ME/CFS patients, with a higher low frequency power of HRV (LFP) and a lower high frequency power of HRV (HFP). This corresponds with other studies that suggest a decreased HRV is present in ME/CFS, indicative of a chronically high sympathetic tone (78, 330, 332–344). Hence, the results of the meta-analysis may indicate reduced vagal modulation in ME/CFS, along with increased sympathetic modulation of heart rate (329).

Autonomic changes in ME/CFS are likely to cause an overall effect of vasoconstriction and resultant hypoperfusion (58), which is central to the pathology of ME/CFS (183) (Figure 8). Additionally, vascular dysfunction, endothelial dysfunction, and microclot presence may also promote vasoconstriction and tissue hypoxia. When skeletal muscle is hypoperfused, metabolites accumulate and trigger muscle metaboreflex activation (MMA) (58) to increase the arterial pressure. If preload failure exists in ME/CFS, it is likely that MMA cannot achieve a sufficient rise in perfusion by increasing stroke volume; hence the only way to increase the blood pressure is via further vasoconstriction. This is worsened when ME/CFS patients are upright, as the baroreflex is activated (345), further promoting vasoconstriction in skeletal muscle. Additionally, when B2AdR is dysfunctional, it aggravates the situation by inhibiting vasodilation in skeletal muscle (58). Therefore, three factors cause excessive vasoconstriction: B2AdR dysfunction, excessive baroreflex activation due to hypovolemia, and excessive MMA activation due to the poor metabolic situation. With a chronically high sympathetic tone, there is then a need for sympatholysis in skeletal muscles to prevent vasoconstriction via the α1-adrenegeric receptors (58). Sympatholysis enhances the release of local endogenous, short-lived vasodilators such as adenosine, ATP, prostaglandins, prostacyclin, bradykinin, and protons to act as a compensatory mechanism (58). However, if these vasodilators enter the systemic circulation, they could contribute to ME/CFS symptoms such as fatigue, flu-like symptoms, pain, fever, and sleep disturbances, similar to the effects observed when vasodilators spill over in dysmenorrhea (346). An example of this effect can be observed with bradykinin (purple box within Figure 8) (347, 348), and preload failure experienced in ME/CFS may be correlated with the endogenous vasodilator substances produced in skeletal muscles.

Figure 8

58, 78, 183, 330, 332–348). Created with Biorender.com. B2AdR, beta-2 adrenergic receptor; ED, endothelial dysfunction; HRV, heart-rate variability; HSP, heat shock protein; IL, interleukin; KKS, kallikrein-kinin system; M3, muscarinic acetylcholine receptor M3; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; MMA, muscle metaboreflex activation; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; SV, stroke volume; TNF, tumour necrosis factor.

Abnormal coagulation: the role of microclots and inflammagens in circulation that cause pathological clotting

It has been hypothesised that hypercoagulation plays a significant role in ME/CFS (349–351), but there are still discrepancies between studies (352). Hence, there is a need to investigate this matter in greater detail. In one study, ME/CFS blood samples displayed significant hypercoagulability in thromboelastography (TEG) analyses of both whole blood and platelet poor plasma (313). Platelet hyperactivation was also observed, as well as the presence of microclots containing fibrinogen and amyloid proteins. The area of these “fibrinaloid” microclots was found to be greater in ME/CFS samples in comparison to healthy controls (313).

As mentioned previously, elevated levels of LPS molecules in ME/CFS patients have been documented (191) with increased levels of IgM and IgA antibodies to LPS in serum (205). LPS can directly and acutely bind to plasma proteins such as fibrinogen to promote the formation of these “fibrinaloid” microclot deposits (353). Hence, not only does LPS induce chronic inflammation via cytokine production; it also has a hypercoagulatory effect by binding to plasma proteins. Since these “fibrinaloid” microclots are usually more resistant to fibrinolysis, they are hypothesised to linger in the circulation and have extended contact with the endothelium (313). Hence, the microclots may result in decreased circulation and blockage of the microcapillaries, resulting in ischemia and therefore many symptoms of ME/CFS, as seen in Figure 9.

Figure 9

Neuroinflammation

PET imaging has displayed elevated cytokines in the spinal cord and brain (46, 354), as well as increased activation of astrocytes (46, 354) and microglia (46, 47, 354). Although cytokines are mainly produced by the immune system, there is also an unclear link between neuroinflammation and these peripheral proinflammatory cytokines (46) and some cytokines may also be produced in the CNS (201). These cytokines can promote cognitive dysfunction as they are able to disrupt the blood-brain barrier (BBB), allowing proinflammatory cytokines (52), cells (such as dendritic, B cells, and T cells) (52), and gut microbes or toxins (355) to translocate into the brain and promote inflammation (Figure 10). One in vitro study found that EBV dUTPase altered the expression of 34 genes with roles related to BBB integrity (137). Hence, EBV UTPase may alter the synaptic structure and function in ME/CFS, as well as dysregulate neuronal communication, influencing cognitive processes.

Figure 10

45, 47, 52, 201, 251, 354, 355). Created with Biorender.com. BBB, blood-brain barrier; IL, interleukin; iNOS, inducible nitric oxide synthase; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NMDA, N-methyl-D-aspartate; TNF-α, tumour necrosis factor alpha.

Such inflammatory changes potentially cause impaired autoregulation of blood flow (29), hypoperfusion in the brain stem (356–358), and brain tissue hypoxia (22, 23, 26, 29–101, 103, 109, 113, 127–234, 248–256, 266, 297–318, 329–359).

Tilt tests of ME/CFS patients have shown a reduced cerebral blood flow (360) and elevated intracranial pressure (361, 362). These changes may cause disordered sympathetic and parasympathetic activity (158, 360) as well as PEM and cognitive dysfunction (29). Likewise, such neuroinflammation can interact with neurotransmitters, elevate procoagulant activity and thrombosis, and cause endothelial damage, resulting in neurovascular coupling (NVC) dysfunction (363).

Impaired energy metabolism in ME/CFS

Even though an exact metabolic phenotype has not been established (185), a stressed metabolism is present in ME/CFS. When threats to homeostasis occur such as infection, hypoxia, and starvation (364, 365), they involve immune and inflammatory processes that influence energetics and metabolism (366, 367). In the case of ME/CFS, this energy strain may be a consequence of exertion-sensitive tissue hypoxia, leading to systemic patterns of metabolic adaptation and compensation (185). It is thought that over time, the disease shifts from an early hypermetabolic state to a hypometabolic state with decreased metabolites (251) and reduced energy production (59), correlating with patient clinical profiles (185).

Mitochondrial dysfunction is a prominent feature in ME/CFS (60, 368–375). It is known to exacerbate inflammation and redox imbalances (251) by triggering the NLR family pyrin domain containing 3 (NLRP3) inflammasome (251), increasing the release of inflammatory cytokines such as IL-1β and IL-18 (376). Additionally, damaged mitochondria release mtDNA into the cytosol, activating the innate immune system via damage-associated molecular patterns (DAMPs) (251, 377), modulating both innate and adaptive immune responses (377–379). Moreover, mitochondrial damage elevates ROS levels (380), which can in turn damage mtDNA and proteins that may be involved in the electron transport chain (ETC), resulting in lowered ATP production and decreased energy levels (381).

This mitochondrial dysfunction is a result of structural and functional changes. Structural mitochondrial abnormalities have been seen in muscle biopsies from ME/CFS patients (382), but this is not observed in other studies (383). More condensed mitochondrial cristae were observed in blood cells from ME/CFS patients, but the mitochondrial crista length, sise, shape, density, membrane potential, and enzymatic activities of the complexes inside the ETC remained intact (384). In CD4+ T cells, mitochondrial mass was also not altered in ME/CFS (254).

Metabolic abnormalities are evident in ME/CFS, such as reduced mitochondrial respiratory function in ME/CFS neutrophils (371, 375) and PBMCs (385). Although mitochondrial respiration was noted as unchanged in resting and stimulated CD4+ and CD8+ T cells, CD8+ T cells were found to have a reduction in proton leak, ATP synthesis, and mitochondrial membrane potential (254). Decreased ATP production has also been noted in lymphoblasts (386) and PBMCS (387). Additionally, decreased glycolysis has been observed in CD8+ T cells at rest and after activation (254), CD4+ T cells at rest (254), blood and urine samples (187), and PBMCs (388). Similarly, a decreased glycolytic reserve has been found in NK cells from ME/CFS patients (389) and metabolomic analyses have revealed compromised ATP production via the tricarboxylic acid (TCA) cycle (389). These dysfunctions may arise from impaired pyruvate dehydrogenase (PDH) function identified in muscle cells (390) and serum (184), as well as reduced plasma coenzyme Q10 (CoQ10) levels in ME/CFS blood and plasma (372, 391) that is inversely associated with fatigue severity (391). Abnormal oxidative phosphorylation may also occur in neutrophils (371, 375) and PBMCs (388).

If such aerobic metabolism is impaired, the body switches to anaerobic production which generates nominally 18 times less ATP per glucose molecule and produces more lactic acid (392). Two-day cardiopulmonary exercise tests (CPET) have practically demonstrated this reduced anaerobic threshold in ME/CFS (393, 394). Some clinical studies have found elevated lactate levels (395, 396) in ME/CFS patient blood, cerebrospinal fluid, and muscles, suggesting there is reduced oxidative phosphorylation and a switch to anaerobic glycolysis (392, 397–399). Moreover, elevated serum lactate dehydrogenase (LDH) has been observed (400), suggestive of tissue destruction, along with elevated lactic acid levels (47, 397, 401). However, the relationship between lactic acid levels and ME/CFS is still being investigated, as another study reported reduced lactic acid levels in urine, along with lower pyruvate and alanine (187). Additionally, it is worth considering that heightened lactic production, in conjunction with its clearance during rest and exercise, may function in a compensatory manner with lactic acid acting as an energy source. Skeletal muscle acidosis and dysregulated protons have also been found in patients during or after exercise (401–404).

On the other hand, there is also altered utilisation of amino acids and fatty acids as catabolic fuel (184, 186). These studies hypothesised that this impaired PDH activity in ME/CFS may result in increased amino acid utilisation as an energy source. Metabolomic studies have displayed this altered cellular energetics, but the affected metabolites differ between studies (186, 269, 405–407). Some affected metabolites link to amino acid metabolism and changes in key pathways such as amino acid metabolism has been observed (184, 187, 408, 409). Changes in blood glucose and lipids indicate a metabolic shift (405, 406, 410, 411) as there are reduced levels of acyl-carnitine and fatty acids (412), and amino acids from the urea cycle (187, 408). In essence, energy fuel storage, mobilisation, and utilisation may be altered in ME/CFS patients.

This energy impairment likely results in a hypometabolic state as the illness progresses (59, 401, 407, 413), called the “cell danger response” (414–416). This state may be secondary to a persisting stressor, such as a redox imbalance (251), persistent infection (201, 251), injury (201), insufficient nutrients (201), cold temperatures (201), or it could be due to a defect in the “switch” that turns off this protective state (251). However, the reduced blood flow and resulting ischaemia may also act as a stressor itself. This cell danger response is an evolutionary adaptation enabled to protect the cells and host from harm (414–416). At the level of the organism, this is called the “integrated stress response” (ISR) (417). In this process, non-essential energy-consuming mechanisms are reduced, allowing energy molecules to be used for mechanisms that are crucial for viability. Neuroinflammation or fever is presumed to also trigger ISR, as autoantibodies may target neural or immune systems and cause inflammation elsewhere (418). Since redox imbalance is a mechanism involved in ME/CFS, it may be an indication of systemic inflammation in response to persistent infection or injury (251).

Even though mitochondrial dysfunction appears evident in ME/CFS, the causes of such dysfunction are speculative (251) and there is inconsistent evidence correlating mitochondrial dysfunction and ME/CFS (254, 283, 386, 389, 419). In addition, mitochondria modulate intracellular calcium homeostasis and immune regulatory pathways (420, 421), which means these pathways may too be compromised in ME/CFS.

Hormonal alterations

Since stress has been described as a potential trigger for ME/CFS (422) and cause of symptom flare-ups (423, 424), it is likely that the HPA axis- the neurobiological stress system- may be implicated in ME/CFS (53, 425, 426), as well as abnormalities in growth hormone (GH) secretion and dysfunctional adrenergic metabolism (255). Immune and inflammatory responses in the blood are mediated by the HPA axis to prevent any autoimmune alterations (63). If the presence of an initial stressor is prolonged, the HPA axis will become chronically activated and trigger the overproduction of cortisol which, over time, will result in a reduction in cortisol levels (427). It is thought that hormonal changes such as this hypocortisolism may result in symptoms of fatigue experienced by patients (255, 428, 429). A potential negative feedback loop, often colloquially referred to as a “stress crash” or “adrenal burnout”, is likely to develop. However, it is important to note that “adrenal burnout” is not an official medical diagnosis, and the mechanisms involved may not directly involve the adrenals experiencing complete exhaustion (63). Chronic HPA activation elevates cortisol production, lowering immune responses and the production of proinflammatory cytokines. However, the HPA axis will then respond to these heightened cortisol levels by decreasing the production of cortisol over time. This will reduce the protection provided by the HPA axis, attenuating immune and inflammatory changes, and leaving ME/CFS patients more vulnerable to minor stressors (429). It is also possible that HPA sensitivity rather than HPA axis dysfunction exists in patients (63).

In one ME/CFS study, significantly lower levels of adrenocorticotropin (ACTH)/cortisol were found (430). GH peak/insulin-like growth factor-1 (IGF-1) were also significantly reduced in severe ME/CFS patients compared to controls and ME/CFS patients with mild disease. GH/IGF-1, and particularly IGF-1, play various roles in neurons such as neuroprotection, mitochondrial protection, antioxidant defence, and reduction in CNS inflammation (431). Hence, a reduction in these hormones would result in these beneficial mechanisms being reduced (430). Similarly, impaired GH release after exposure to dexamethasone was also found in patients exposed to organophosphates (153). GH is secreted from somatotrophs in the anterior pituitary gland and is influenced positively by growth hormone-releasing hormone (GHRH) and inhibited by somatostatin. Exercise and stress with B-adrenergic stimuli decrease GH secretion by elevating somatostatin tone. Hence, impaired release of GH in these toxin-exposed patients may suggest lowered responsivity of CNS type II glucocorticoid receptors (153).

Serotonin also plays a role in the CNS and controls many stress mechanisms such as the HPA axis through stimulation of corticotropin-releasing hormone (CRH) (432). It is proposed that the production and recycling of dopamine and serotonin is implicated in ME/CFS, which could also be triggered by the EBV dUTPase protein (137). Although an imbalance of these hormones is likely present in ME/CFS, it is unclear whether they are found in elevated or lowered concentrations. One article proposed that excessive serotonin levels could explain classic symptoms of ME/CFS (433), as it would promote the release of excess CRH, and therefore cause chronic reactivation of the HPA axis (434). Furthermore, this excess serotonin could eventually lead to dysregulation of its production (435). Excess serotonin can result in decreased control of various functions, including dysfunctional muscle contraction, migraines, sleep issues, dyspnea, hyperalgesia, and cognitive dysfunction (435). Heightened serotonin levels can also promote the release of dopamine and norepinephrine, resulting in changes to memory, GI problems, mood, and blood coagulation (436). However, lowered dopamine levels are associated with fatigue (437), a commonly present symptom of ME/CFS.

Exposure to toxins such as organophosphates, which are cholinesterase inhibitors, prolongs and amplifies the effects of acetylcholine (153). Acetylcholine is responsible for mood regulation, psychomotor activity, and sleep (438), by activation of central muscarinic receptors, rather than nicotinic receptors (153). Acetylcholine is also known to promote GH secretion (439). However, patients exposed to organophosphates experience a heightened GH response to pyridostigmine (153). It is possible that the somatotrophs developed increased sensitivity to GHRH as pyridostigmine causes intermediate stimulation of GHRH. Alternatively, the more supported hypothesis is that there could be hyper-responsivity of the cholinergic receptors at a hypothalamic level, causing a greater decrease in somatostatin tone, and elevated GH release from the anterior pituitary gland (153).

Various symptoms seen in ME/CFS, such as changes in body weight, appetite, fluid retention, and irregular menstruation, are also observed in hypothalamic dysfunction (440). Dysfunctional hypothalamic function can be seen in ME/CFS patients in the form of up-regulation of hypothalamic 5-hydroxytryptamine (5-HT) receptors (441) and abnormal arginine/vasopressin responses to deprivation tests and water loading (440). However, when the 5-HT-releasing agent D-fenfluramine is used in patients experiencing a neurobehavioral syndrome after exposure to organophosphates, elevated sensitivity of central 5-HT receptors is observed (442).

It is also possible that hypothalamic/pituitary autoimmunity may be present in ME/CFS- particularly in the more severe cases- as antipituitary and antihypothalamic antibodies have been identified (430). Additionally, if gut permeability is indeed increased in ME/CFS patients, microbes and antigens may be able to cross the epithelial barrier into surrounding tissue and blood, potentially crossing the BBB and altering the HPA axis (443). Hence, GI dysbiosis may also promote HPA axis activation (63).

Immune dysfunction

Since one of the most supported hypotheses for the origin of ME/CFS is bacterial or viral (85, 99, 444) infection (94); immune dysregulation has been linked to ME/CFS patients (201, 255) (Table 2) (Figure 11), it is possible that infectious organisms result in chronic symptoms by interfering with host gene expression, immunity, and metabolism (25). More evidence of an infectious aetiology can be seen in the alteration of the number and function of various immune cells, immune profiles, and autoimmune parameters (294, 486). It has been noted that these abnormal immune responses may be more pronounced within the first three years of the disease; as the disease becomes prolonged, these abnormalities appear to subside and T-cell exhaustion becomes evident (225, 254). This suggests that the overactive immune response eventually becomes exhausted or overcome by counter-regulatory mechanisms. Since a link between infections and autoimmune diseases has been well established, this correlation could explain the presence of autoimmune symptoms in ME/CFS (487). However, the measurement of the innate and adaptive immune responses in ME/CFS patients has resulted in conflicting abnormal results (235). Although immune dysfunction is clear in ME/CFS, further studies using defined cohorts, standardised assays, and new technologies are required to determine specific patterns (30). Furthermore, the use of antiviral drugs to treat ME/CFS has been unsuccessful (488), contradicting the hypothesis that ME/CFS could be caused by a clearance failure of the pathogenic microbe (99, 107). A further hypothesis is that ME/CFS could include misdirected immune responses to the initial infection, resulting in a chronic autoimmune disease with molecular mimicry (the “hit and run” hypothesis) (85).

Figure 11

25, 52, 201, 278, 445–461, 465–467, 469, 483–485). Created with Biorender.com. BCR, B cell receptor; EBV, Epstein-Barr virus; HLA-DR, human leukocyte antigen- DR isotype; IL, interleukin; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; MHC, major histocompatibility complex; TCR, T cell receptor; TGF-β, transforming growth factor-β; Treg, regulatory T cell.

Autoimmunity

Upregulation of autoimmune genes

As in other chronic disorders, some genes in ME/CFS patients have been found to be associated with autoimmunity, such as the HLA alleles (30). In ME/CFS, an increased prevalence of the class II major histocompatibility complex HLA-DQB*01 allele (88), along with two other variants of HLA-DQB1 in combination with two RAGE-374A variants (489) was found. Although some authors have tried to assess the mechanistic link between HLA-II allele expression and the development of ME/CFS, the lack of robust data makes it difficult to support this association (88, 490). Single nucleotide polymorphisms (SNPs) in receptors, enzymes, and transcription factors are also known to cause loss or gain of functions (30) that can increase the risk of autoimmune disease development (491–495). If such changes occur in T cell development, B cell activation and proliferation, or cytokine signalling, it may result in the development of autoimmune diseases. In ME/CFS, SNPs in TLR signalling pathways, the complement cascade, and cytokines have been identified (74, 496).

As mentioned, infectious mononucleosis caused by EBV is a risk factor for various autoimmune diseases (487, 497), and may play a potential role in ME/CFS (140, 498–500). After being infected by EBV, some ME/CFS patients have upregulation of the EBV-induced gene 2– an important gene in immune and CNS function (25). Hence, such gene induction may correlate with various neurological and immune-related symptoms of ME/CFS, as an estimated 38-55% of ME/CFS patients have symptoms that overlap with other autoimmune diseases (501). Similarly, one study illustrated an enhanced IgG reactivity against an EBV repeat sequence, EBNA-6, suggesting that homologous sequences of various human proteins with this repeat sequence might be useful targets for antigenic mimicry (85).

Autoantibody presence

It has been proposed that ME/CFS is a variant of an autoimmune mechanism (29). Typical autoimmune diseases have characteristic pathogenic IgGs correlated with inflammation, tissue injury, and complement activation. Such persistent autoantibodies are hypothesised to disturb vessel autoregulation, causing secondary metabolic and autonomic adaptations. Although these typical changes are not necessarily characteristic of ME/CFS, another autoimmune mechanism may exist in ME/CFS that affects the autonomic control of blood vessel tone and flow autoregulation. Hence, autoimmunity is considered important in the pathology of ME/CFS (30, 85, 182).

In some ME/CFS patients, autoantibodies have been identified, including those against antinuclear antibodies (502–505). These autoantibodies are hypothesised to target nuclear, membrane, and neurotransmitter receptor structures (30, 255). Double-stranded DNA antibodies have also been found in 12% of ME/CFS patients (506), although other studies have failed to find such antibodies in ME/CFS (0.7%) (507). Single-stranded DNA antibodies have also been identified (505), along with anti-ganglioside antibodies (508), autoantibodies against endothelial and neuronal cells (506), and phospholipid autoantibodies (506, 508, 509). Antibodies against cardiolipin were also found in 92-95% of ME/CFS patients (509, 510), although they were only 4% in another study (506). Additionally, antibodies have been identified against human nuclear dUTPase and nuclear envelope protein lamin B1 (511). Hence, this autoantibody presence especially targets the autonomic and central nervous systems (503), which may explain the dysautonomia and immune dysregulation present in ME/CFS (58).

In other autoimmune diseases, natural antibodies are found against adrenergic, muscarinergic, and other G protein coupled receptors (GPCR) (30, 512). In some ME/CFS patients, such antibodies against neurotransmitter receptors have been identified, such as against the muscarinic M1AChR (504), M3AChR (58, 359, 503), and the adrenergic B2AdR (58, 359, 503). The presence of these autoantibodies potentially results in dysfunction in these receptors (58, 513). However, no difference between ME/CFS patients and controls was found with respect to autoantibodies against serotonin, angiotensin, endothelin, mu-opioid, and dopamine (503, 504). Although, autoantibodies against serotonin have been associated with ME/CFS (506, 508).

Various general autoantibodies have also been identified in ME/CFS, such as those against cellular components including anchorage molecules (514), HSP-60 (515), microtubule associated protein 2 (516), cardiolipin in 92-95% of ME/CFS patients in two studies (509, 510) but only 4% in another study (506), and neo-antigens (517). Moreover, 30% of ME/CFS patients in one study were identified to have antibodies against endothelial cells (506). If autoimmunity is present in ME/CFS, it may increase intestinal permeability (518) and explain the various GI manifestations (190).

Soluble autoimmunity markers

B lymphocyte activating factor (BAFF) has been identified in many autoimmune diseases (519) as it regulates survival and maturation of B cells to control the IL-10 production of regulatory B cells (520, 521). Some ME/CFS patients have displayed elevated BAFF, but the gene expression of the BAFF receptor (TNFRSF13C) has been shown to be reduced in ME/CFS patients, suggesting that the elevated serum BAFF is a compensatory mechanism. However, the link between BAFF and autoantibodies in ME/CFS is yet to be investigated (30). Members of the TGF-β family- Activin A and B- are known to control inflammation and muscle mass (522). Heightened levels of activin A and B have been found in ME/CFS with an elevated ratio of activin A or B to the binding protein follostatin (523). Although no causal role has been established, activin A is a pleiotropic cytokine known to influence immune regulation and is altered in various autoimmune and inflammatory diseases (524). IL-21 is also a pleiotropic cytokine (525) important for differentiation of follicular helper T cells that are essential for the germinal centre antibody response (526). When activin A (527) and IL-21’s (528) processes are dysregulated, it is hypothesised to promote autoimmune and inflammatory diseases, although a causal role is still not shown (527).

Management of ME/CFS

As well as there being insufficient diagnostic testing available for ME/CFS patients, there are also no effective therapies (12, 26, 60, 488, 529–531) and few established non-pharmacological treatments for ME/CFS (11, 29). The lack of awareness (60), paucity of diagnostic tools (60), heterogeneity between patients (26, 60, 529), disbelief from health care workers (60), unpredictable relapses, and multiplicity of symptoms have made it difficult to formulate a treatment for ME/CFS. Hence current advice is aimed at symptom management and lifestyle changes (11). The current available treatments/lifestyle modifications are summarised in Figure 12.

Figure 12

11, 23, 60, 532). Created with Biorender.com. GI, gastrointestinal; PEM, post-exertional malaise.

Disbelief of doctors

Since not enough is known about the risk factors of ME/CFS, it makes primary prevention unlikely (53). However, secondary prevention is possible to reduce diagnostic delay, the incidence of severe and prolonged disease, and costs of care. One way to minimise diagnostic delays is to rectify the disbelief of doctors and the stigmatization around ME/CFS (53, 533, 534). In 1969, the WHO classified ME/CFS as a neurological disease (44) based on the neurological features of the disease. Following this, epidemic cases of ME/CFS were described as “mass hysteria” in 1970 by two psychiatrists, McEvedy and Beard (535). Although these psychiatrists were faulted for inadequately investigating the patients they described (536) and their conclusions were discredited (537–539), this sparked stigmatization of ME/CFS.

Another mistake that doctors sometimes make is to second-guess their initial diagnosis (39). This scenario may arise when doctors experience uncertainty or apprehension about their assessment, potentially leading to ME/CFS patients feeling neglected. This uncertainty or hesitation may prompt doctors to seek confirmation from other professionals, which may create a traumatic experience for the patient and prolong their diagnosis. Although, since ME/CFS is currently diagnosed based on exclusion criteria and subjective symptom assessment, it is sometimes necessary for patients to be referred to other professionals to exclude other possible diagnoses. For example, referral to psychiatrists may be helpful since ME/CFS seems to coexist with anxiety disorders, symptoms of ME/CFS overlap with Major Depressive Disorder (MDD), and patients with severe ME/CFS may also be at risk of developing secondary MDD (36, 532). However, it can also be detrimental referring ME/CFS patients to psychiatrists (39), not because it excludes other diagnoses, but rather if patients are labelled as hypochondriacs and their condition is attributed solely to psychosomatic origins (23). Hence, validation of the patient’s experiences is important. Additionally, friends and family must offer support to patients, such as helping them acquire handicap placards, attain work and school accommodations, make nutritional adjustments, and apply for disability and housing benefits (23).

To manage and live with ME/CFS, it is also important that patients schedule regular trips to their physician to manage their symptoms, as well as discuss complementary approaches the patient may have adopted- such as new supplements (23). This communication is important to minimise any adverse side effects or drug interactions that may occur (540). Additionally, the reassurance of doctors is important, and they should openly address questions related to a patient’s prognosis. This will help patients maximise their functioning and enhance their quality of life (23). It is worth pointing out that more severe patients are likely to tolerate visits to their doctor poorly, and home visits should be undertaken for them.

Pacing/energy management

Several guidelines have been established to guide the management of ME/CFS. However, some of the recommendations have possibly resulted in more harm than good. One controversial form of self-help is physical activity. When ME/CFS was still believed by many to be a psychological disease (23), doctors often prescribed inappropriate “treatments” such as cognitive behavior therapy (CBT) (39, 530), graded exercise therapy (GET) (39, 530), or the Lightning Process (11) to ME/CFS patients. In 2007 for example, the National Institute for Health and Care Excellence (NICE) released a guideline for clinicians and patients where GET was recommended as a treatment (541). GET first establishes a patient’s baseline of physical activity, and this is then stepped up in fixed increments (11). However, these “treatment” strategies have now been strongly criticised for the harm they have caused (542–544), and in October 2021, GET was removed from the revised NICE guidelines (11). Although, it is important to note that while CBT may not be appropriate as a cure for ME/CFS itself, it could be applied in ME/CFS patients to address symptoms or secondary disorders such as MDD (545).

Furthermore, one misleading and now entirely discredited study (546) was the 2011 PACE (Pacing, Graded Activity, and Cognitive Behavior therapy; a Randomised Evaluation) trial (547). In this paper, the therapies were described as safe with 22% of participants recovering and 60-61% of patients experiencing symptom improvement (547, 548). However, there were specific flaws identified in this paper. Without any clear rationale, the study outcome measures were purposefully modified midtrial to alter the findings in favour of their hypothesis (549, 550). Additionally, patients could worsen during the study and still be classified as “recovered” and the study was unblinded with subjective outcomes. Subsequent review of the raw data revealed that the improvement and recovery rates were not significantly different from the control participants. Moreover, 54% to 74% of patients revealed that they experienced harm after GET (543).

Instead, energy management (pacing) is now emphasised for symptom control (11). Pacing is an individualised approach that monitors energy expenditure to reduce the occurrence, duration, and severity of PEM (23). Energy expenditure encompasses physical, social, cognitive, and emotional activity (11). Avoidance of PEM can help decrease fatigue, cognitive difficulties, sleep disruption, and other symptoms of ME/CFS (551). Some patients use energy monitoring and saving devices such as shower chairs and heart rate monitors (552). Although many commercially available trackers such as Fitbit and Garmin encourage exercise and exertion, the Visible application is a recently designed activity monitor for those with chronic illness (553). According to the amended NICE guidelines, an individualised approach is more appropriate for ME/CFS patients (11). If an ME/CFS patient wishes to incorporate physical activity, it should be closely monitored by a team of specialists as over-exertion has the potential to worsen the symptoms of ME/CFS. Hence, it is the patient’s responsibility to gauge their activity levels while a physiotherapist or occupational therapist oversees the activity. Additionally, patients should be wary of potential relapses or flare-ups to prevent worsening of symptoms.

Nutraceuticals and pharmacological approaches

Many ME/CFS patients take nutritional supplements (530). Vitamin D supplementation can help prevent a vitamin D deficiency (11, 39). If bedbound for extended periods of time, bisphosphonates can also help reduce the risk of osteoporosis (39). If toxin exposure is thought to have triggered the development of ME/CFS, nutritional supplementation of zinc and magnesium may be beneficial in the prophylaxis and therapy of cadmium exposure (154). More research is required around nutraceuticals to optimise their dosages.

Despite there being no U.S. Food and Drug Administration (FDA)-approved treatments for ME/CFS (40), in many cases the symptoms and comorbidities experienced by patients can be treated (24). However, it is important that any medication should be introduced at low dosages as many ME/CFS patients are extremely drug sensitive (23), making them vulnerable to adverse side effects. Since ME/CFS was psychologised at first, many patients were initially treated with antidepressants (60). This misdiagnosis resulted in adverse side effects and dependence on the drug. However, antidepressants are still sometimes prescribed to help if patients are experiencing depression (39).

Treating comorbidities

ME/CFS displays an overlap with several autoimmune or immune-mediated diseases that also have chronic fatigue as a main symptom, such as Hashimoto’s thyroiditis (530), fibromyalgia (FM) (532, 554–557), Mast Cell Activation Disorder (532), sleep apnoea (532), IBS (532), secondary depression or anxiety (532), Ehlers-Danlos syndrome (532), and PoTS (532, 558–563). One ME/CFS speciality clinic found 84% of 960 patients presented with at least one other comorbid condition, often resulting in worsened health (3). Hence, more research on ME/CFS is required to separate it from other diseases that are also associated with chronic fatigue. Treating some of these comorbidities will not cure ME/CFS but might alleviate some of their symptoms and improve some quality of life (23).

Potential therapies

Although some researchers have attempted to establish a treatment for ME/CFS and no reproducible results have been found (60), some treatments seem promising in ME/CFS (Figure 13). Additionally, not many trials meet the clinical design standards to be considered credible. Although no causation has been established for ME/CFS, as the knowledge around the disease expands, so will the potential treatment avenues. Hence, pathways and mechanisms need to be investigated for possible pharmacological intervention. Considering the heterogeneity among ME/CFS patients, however, it is unlikely that one treatment will suit all ME/CFS patients.

Figure 13

22, 29, 29, 30, 84, 193, 530, 564–580). Created with Biorender.com. IgG, immunoglobulin G; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NK, natural killer; NO, nitric oxide; PPAR, peroxisome proliferator-activated receptor; TLR3, toll-like receptor 3; VDR, vitamin D receptor.

Future research recommendations

Most of the research and clinical studies conducted on ME/CFS have inconsistent outcomes and use different study parameters, making the results difficult to compare or combine (11). Most studies are limited owing to their insufficient sample sises, short follow-up times, high dropout rates, inappropriate definitions of recovery, and inclusion of patients with varying conditions (581, 582). Additionally, the small cohort in many studies along with limited comparison groups with other fatiguing illnesses cause inconsistent findings (201). To improve their reproducibility, studies need to use uniform clinical and research criteria, standardise sample collection, and use thorough statistical analyses (305).

Although the research surrounding ME/CFS has increased in the last decade (29), there is still a significant lack of funding for research surrounding ME/CFS (60). In the U.S., the National Institutes of Health (NIH) receives an overall budget of 42 billion dollars. However, in 2019, they only budgeted 15 million dollars towards ME/CFS research, whereas 111 million dollars and 94 million dollars was donated to MS and RA research, respectively (both of which already have drugs on the market). More research is required to define and diagnose ME/CFS as a serious chronic illness (25), as it is uncertain how many patients diagnosed with ME/CFS have an accurate diagnosis (57). Not only does the diagnosis of ME/CFS need to be more accurate, but it also needs to be timely to ensure an earlier diagnosis before a prolonged disease progression occurs (11). Standardisation in diagnosis and disease severity is required to create robust and reproducible results. In combination, more effort needs to be made to include correctly matched controls. For example, since age, lifestyle, medication, geography, and diet are all able to impact microbiome function and composition (583–585), detailed descriptions of food consumption at least 48 hours before the sample collection should be included. Moreover, no defined clinical criteria for ME/CFS makes it even more complicated to compare various study results (52). Additionally, a large GWAS in ME/CFS is desperately needed to assess the biomolecular mechanisms of ME/CFS (56). One study aiming to achieve this is the DecodeME study that launched September 2022 (586). This study aims to pinpoint genetic causes of ME/CFS by testing more than 25,000 DNA samples (586), as a large cohort will help achieve statistical power with reproducible and rigorous results (52). Similarly, identifying microbiomes in ME/CFS blood and brain tissue should be prioritised in ME/CFS research (193). Since some of the main components of ME/CFS include redox imbalance, chronic inflammation, and defective energy metabolism, it is also important to investigate how these components interact bidirectionally (201).

One thing to consider is that because ME/CFS is a severely disabling disease, many patients are house or bedbound and are unable to visit the clinics multiple times for follow-up analyses (39), even though these very severe cases are estimated to be around 25% of the ME/CFS cases (11, 39, 587). It is important to make research more available for this percentage of ME/CFS cases, since they are the most severely affected by the disease and these severe cases are rarely studied (10). It is likely that as the condition worsens, so the probability of identifiable biomarkers for the disease increases, making it crucial to study severely ill patients. ME/CFS needs to be more patient-centered, involving patients in clinical decisions regarding their treatment (11, 53). There is also concern that the COVID-19 pandemic may increase the number of people suffering from ME/CFS (588). Similarly, with the growing emergence of Long COVID cases, many Long COVID symptoms are coinciding with those present in ME/CFS (29). More research is required to determine whether these symptoms are caused by subtle organ damage from the viral infection, or whether these Long COVID patients have a postinfectious immune disturbance whose pathomechanisms is like that in ME/CFS.

It is also important to break the negative stigma that is associated with ME/CFS. ME/CFS is a remarkably misunderstood disease, and many patients have experienced judgement, prejudice, and disbelief from healthcare professionals (11, 39) as some refuse to view ME/CFS as an indisputable clinical entity (39) and question its legitimacy (25). This disbelief and misjudgment (40, 58) delays any possible early diagnosis for the patients and has also resulted in psychologisation of the disease (11, 40, 53). Health and social care professionals need to acknowledge that their patients are living with ME/CFS, and how they have symptoms that severely affect them (11). Hence, they should take time to build empathetic relationships with their patients.

Finally, it is imperative to provide increased support to the ME/CFS community, a necessity that is steadily growing alongside the establishment of research groups and charitable organisations dedicated to aiding ME/CFS patients. One multidisciplinary team consisting of ME/CFS researchers and health professionals, the European Network on ME/CFS (EUROMENE), aims to evaluate healthcare for ME/CFS in Europe, improve research and services in the field, and grasp socioeconomic and clinical dimensions of the disease to issue recommendations accordingly (589). The Open Medicine Foundation is another collaborative effort dedicated to advancing medical research on ME/CFS, fostering engagement within the patient community, and promoting education about the condition (590). The Charité Fatigue Centre in Berlin not only conducts clinical research, but also offers support to both patients and doctors in diagnosing and treating ME/CFS, making it an invaluable interdisciplinary network (591). Additionally, registered charities such as the Austrian “WE&ME” Foundation are dedicated to financing ME/CFS research endeavors and raising awareness about the condition (592). Similarly, “Action for M.E.” in England and Wales aim to spread awareness and education around ME/CFS and raise funds to support these patients and their families. They have also recently worked together with the James Lind Alliance non-profit organisation, ME/CFS clinicians, and ME/CFS sufferers and caretakers to identify ME/CFS research priorities (593). The top three research priorities were found to be (1) understanding the biological mechanism behind PEM and how this can be treated or managed (2), which existing drugs used for other conditions would be useful in treating ME/CFS, and (3) finding accurate and reliable diagnostic testing for ME/CFS. Hence, future research should include recommendations such as these with personal input from ME/CFS sufferers.

References

• 1

  ClaytonEW. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. Jama. (2015) 313:1101–2. doi: 10.1001/jama.2015.1346

  • CrossRef
  • Google Scholar
  • View reference in article

• 2

  S. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic FatigueP. Board on the Health of Select and M. Institute of, The National Academies Collection. Reports funded by national institutes of health, beyond myalgic encephalomyelitis/Chronic fatigue syndrome: redefining an illness, national academies press (US). Washington (DC: National Academy of Sciences (2015).

  • Google Scholar
  • View reference in article

• 3

  BatemanLDarakjySSKlimasNGPetersonDLLevineSMAllenAet al. Chronic fatigue syndrome and co-morbid and consequent conditions: evidence from a multi-site clinical epidemiology study. Fatigue: Biomedicine Health Behav. (2015) 3:1–15. doi: 10.1080/21641846.2014.978109

  • CrossRef
  • Google Scholar
  • View reference in article

• 4

  ValdezARHancockEEAdebayoSKiernickiDJProskauerDAttewellJRet al. Demographics, and costs of ME/CFS using large scale medical claims data and machine learning. Front Pediatr. (2018) 6:412. doi: 10.3389/fped.2018.00412

  • CrossRef
  • Google Scholar
  • View reference in article

• 5

  JasonLAKatzBZSunnquistMTorresCCotlerJBhatiaS. The prevalence of pediatric myalgic encephalomyelitis/chronic fatigue syndrome in a community−Based sample. Child Youth Care Forum. (2020) 49:563–79. doi: 10.1007/s10566-019-09543-3

  • CrossRef
  • Google Scholar
  • View reference in article

• 6

  NaculLCLacerdaEMPhebyDCampionPMolokhiaMFayyazSet al. Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care. BMC Med. (2011) 9:91. doi: 10.1186/1741-7015-9-91

  • CrossRef
  • Google Scholar
  • View reference in article

• 7

  BakkenIJTveitoKGunnesNGhaderiSStoltenbergCTrogstadLet al. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. BMC Med. (2014) 12:167. doi: 10.1186/PREACCEPT-1843684980131041

  • CrossRef
  • Google Scholar
  • View reference in article

• 8

  LimE-JSonC-G. Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Trans Med. (2020) 18:289. doi: 10.1186/s12967-020-02455-0

  • CrossRef
  • Google Scholar
  • View reference in article

• 9

  JasonLARichmanJARademakerAWJordanKMPlioplysAVTaylorRRet al. A community-based study of chronic fatigue syndrome. Arch Intern Med. (1999) 159:2129–37. doi: 10.1001/archinte.159.18.2129

  • CrossRef
  • Google Scholar
  • View reference in article

• 10

  PendergrastTBrownASunnquistMJantkeRNewtonJLStrandEBet al. Housebound versus nonhousebound patients with myalgic encephalomyelitis and chronic fatigue syndrome. Chronic Illn. (2016) 12:292–307. doi: 10.1177/1742395316644770

  • CrossRef
  • Google Scholar
  • View reference in article

• 11

  NICE. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management (NICE guideline [NG206]). (2021).

  • Google Scholar
  • View reference in article

• 12

  RowePCUnderhillRAFriedmanKJGurwittAMedowMSSchwartzMSet al. Myalgic encephalomyelitis/chronic fatigue syndrome diagnosis and management in young people: A primer. Front Pediatr. (2017) 5:121. doi: 10.3389/fped.2017.00121

  • CrossRef
  • Google Scholar
  • View reference in article

• 13

  Centers for Disease Control and Prevention. Myalgic encephalomyelitis/chronic fatigue syndrome. U.S. Department of Health & Human Services. (2023).

  • Google Scholar
  • View reference in article

• 14

  BhuiKSDinosSAshbyDNazrooJWesselySWhitePD. Chronic fatigue syndrome in an ethnically diverse population: the influence of psychosocial adversity and physical inactivity. BMC Med. (2011) 9:26. doi: 10.1186/1741-7015-9-26

  • CrossRef
  • Google Scholar
  • View reference in article

• 15

  CarruthersBMJainAKDe MeirleirKLPetersonDLKlimasNGLernerAMet al. Myalgic encephalomyelitis/chronic fatigue syndrome. J Chronic Fatigue Syndrome. (2003) 11:7–115. doi: 10.1300/J092v11n01_02

  • CrossRef
  • Google Scholar
  • View reference in article

• 16

  CarruthersBMSandeMIvdeMeirleirKLDeKlimasNGBroderickGMitchellTet al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. (2011) 270:327–38. doi: 10.1111/j.1365-2796.2011.02428.x

  • CrossRef
  • Google Scholar
  • View reference in article

• 17

  KeechASandlerCXVollmer-ConnaUCvejicELloydARBarryBK. Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome. J Psychosomatic Res. (2015) 79:537–49. doi: 10.1016/j.jpsychores.2015.08.008

  • CrossRef
  • Google Scholar
  • View reference in article

• 18

  JasonLABentonMCValentineLJohnsonATorres-HardingS. The economic impact of ME/CFS: individual and societal costs. Dyn Med. (2008) 7:6. doi: 10.1186/1476-5918-7-6

  • CrossRef
  • Google Scholar
  • View reference in article

• 19

  The Optimum Health Clinic (OHC). Counting the cost: chronic fatigue syndrome/myalgic encephalomyelitis. (2017).

  • Google Scholar
  • View reference in article

• 20

  HickieILloydAHadzi-PavlovicDParkerGBirdKWakefieldD. Can the chronic fatigue syndrome be defined by distinct clinical features? Psychol Med. (1995) 25:925–35. doi: 10.1017/S0033291700037417

  • CrossRef
  • Google Scholar
  • View reference in article

• 21

  EdwardsJCMcGrathSBaldwinALivingstoneMKewleyA. The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem. Fatigue. (2016) 4:63–9. doi: 10.1080/21641846.2016.1160598

  • CrossRef
  • Google Scholar
  • View reference in article

• 22

  FukudaKStrausSEHickieISharpeMCDobbinsJGKomaroffA. The chronic fatigue syndrome: a comprehensive approach to its definition and study International Chronic Fatigue Syndrome Study Group. Ann Intern Med. (1994) 121:953–9. doi: 10.7326/0003-4819-121-12-199412150-00009

  • CrossRef
  • Google Scholar
  • View reference in article

• 23

  BatemanLBestedACBonillaHFChhedaBVChuLCurtinJMet al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. (2021) 96:2861–78. doi: 10.1016/j.mayocp.2021.07.004

  • CrossRef
  • Google Scholar
  • View reference in article

• 24

  ChangCJHungLYKogelnikAMKaufmanDAiyarRSChuAMet al. A comprehensive examination of severely ill ME/CFS patients. Healthcare (Basel). 9. (2021). doi: 10.3390/healthcare9101290

  • CrossRef
  • Google Scholar
  • View reference in article

• 25

  WongTLWeitzerDJLongCOVID. and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-A systemic review and comparison of clinical presentation and symptomatology. Medicina (Kaunas). (2021) 57. doi: 10.3390/medicina57050418

  • CrossRef
  • Google Scholar
  • View reference in article

• 26

  BestedACMarshallLM. Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians. Rev Environ Health. (2015) 30:223–49. doi: 10.1515/reveh-2015-0026

  • CrossRef
  • Google Scholar
  • View reference in article

• 27

  RamsayMA. Myalgic encephalomyelitis: A baffling syndrome with a tragic aftermath. ME Assoc. (1981).

  • Google Scholar
  • View reference in article

• 28

  CairnsRHotopfM. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). (2005) 55:20–31. doi: 10.1093/occmed/kqi013

  • CrossRef
  • Google Scholar
  • View reference in article

• 29

  FlugeØ.TronstadKJMellaO. Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Clin Invest 131. (2021). doi: 10.1172/JCI150377

  • CrossRef
  • Google Scholar
  • View reference in article

• 30

  SotznyFBlancoJCapelliECastro-MarreroJSteinerSMurovskaMet al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease. Autoimmun Rev. (2018) 17:601–9. doi: 10.1016/j.autrev.2018.01.009

  • CrossRef
  • Google Scholar
  • View reference in article

• 31

  BrittainEMuirheadNFinlayAYVyasJ. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): major impact on lives of both patients and family members. Medicina (Kaunas) 57. (2021). doi: 10.3390/medicina57010043

  • CrossRef
  • Google Scholar
  • View reference in article

• 32

  KingdonCCBowmanEWCurranHNaculLLacerdaEM. Functional status and well-being in people with myalgic encephalomyelitis/chronic fatigue syndrome compared with people with multiple sclerosis and healthy controls. Pharmacoecon Open. (2018) 2:381–92. doi: 10.1007/s41669-018-0071-6

  • CrossRef
  • Google Scholar
  • View reference in article

• 33

  NaculLCLacerdaEMCampionPPhebyDM.d.L. DrachlerJCPolandFet al. Molokhia, The functional status and well being of people with myalgic encephalomyelitis/chronic fatigue syndrome and their carers. BMC Public Health. (2011) 11:402. doi: 10.1186/1471-2458-11-402

  • CrossRef
  • Google Scholar
  • View reference in article

• 34

  NúñezMNunezEDel ValJLJ. fernandez-huertaCAlegreMRoigDet al. Health-related quality of life in chronic fatigue syndrome versus rheumatoid arthritis as control group. J Chronic Fatigue Syndrome. (2008) 14:31–43. doi: 10.1300/J092v14n02_04

  • CrossRef
  • Google Scholar
  • View reference in article

• 35

  Falk HvidbergMBrinthLSOlesenAVPetersenKDEhlersL. The health-related quality of life for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PloS One. (2015) 10:e0132421. doi: 10.1371/journal.pone.0132421

  • CrossRef
  • Google Scholar
  • View reference in article

• 36

  SteinE. Assessment and treatment of patients with ME/CFS: Clinical guidelines for psychiatrists. Hentet. (2005) 11:13.

  • Google Scholar
  • View reference in article

• 37

  RobertsEWesselySChalderTChangC-KHotopfM. Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register. Lancet. (2016) 387:1638–43. doi: 10.1016/S0140-6736(15)01223-4

  • CrossRef
  • Google Scholar
  • View reference in article

• 38

  CoxDL. Management of CFS: development and evaluation of a service. Br J Ther Rehabil. (1998) 5:205–9. doi: 10.12968/bjtr.1998.5.4.14088

  • CrossRef
  • Google Scholar
  • View reference in article

• 39

  SpeightN. Severe ME in children. Healthcare (Basel) 8. (2020). doi: 10.3390/healthcare8030211

  • CrossRef
  • Google Scholar
  • View reference in article

• 40

  WilliamsLRIsaacson-BarashC. Three cases of severe ME/CFS in adults. Healthcare (Basel) 9. (2021). doi: 10.3390/healthcare9020215

  • CrossRef
  • Google Scholar
  • View reference in article

• 41

  US Food and Drug Administration. The voice of the patient. In: A series of reports from the U.S. Food and Drug Administration’s (FDA’s) patient-focused drug development initiative. Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) U.S. Food and Drug Administration (FDA) (2013).

  • Google Scholar
  • View reference in article

• 42

  VinkMVink-NieseF. Work rehabilitation and medical retirement for myalgic encephalomyelitis/chronic fatigue syndrome patients. A review and appraisal of diagnostic strategies. Diagnostics (Basel). (2019) 9. doi: 10.3390/diagnostics9040124

  • CrossRef
  • Google Scholar
  • View reference in article

• 43

  VyasJMuirheadNSinghREphgraveRFinlayAY. Impact of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on the quality of life of people with ME/CFS and their partners and family members: an online cross-sectional survey. BMJ Open. (2022) 12:e058128. doi: 10.1136/bmjopen-2021-058128

  • CrossRef
  • Google Scholar
  • View reference in article

• 44

  World Health Organization. Manual of the international statistical classification of diseases, injuries, and causes of death based on the recommendations of the eighth revision conference. Geneva: World Health Organization (1969). p. 173.

  • Google Scholar
  • View reference in article

• 45

  NakatomiYKuratsuneHWatanabeY. [Neuroinflammation in the brain of patients with myalgic encephalomyelitis/chronic fatigue syndrome]. Brain Nerve. (2018) 70:19–25. doi: 10.11477/mf.1416200945

  • CrossRef
  • Google Scholar
  • View reference in article

• 46

  NakatomiYMizunoKIshiiAWadaYTanakaMTazawaSet al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: an ¹¹C-(R)-PK11195 PET study. J Nucl Med. (2014) 55:945–50. doi: 10.2967/jnumed.113.131045

  • CrossRef
  • Google Scholar
  • View reference in article

• 47

  MuellerCLinJCSheriffSMaudsleyAAYoungerJW. Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging Behav. (2020) 14:562–72. doi: 10.1007/s11682-018-0029-4

  • CrossRef
  • Google Scholar
  • View reference in article

• 48

  ZeinehMMKangJAtlasSWRamanMMReissALNorrisJLet al. Right arcuate fasciculus abnormality in chronic fatigue syndrome. Radiology. (2015) 274:517–26. doi: 10.1148/radiol.14141079

  • CrossRef
  • Google Scholar
  • View reference in article

• 49

  BuchwaldDCheneyPRPetersonDLHenryBWormsleySBGeigerAet al. A chronic illness characterised by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med. (1992) 116:103–13. doi: 10.7326/0003-4819-116-2-103

  • CrossRef
  • Google Scholar
  • View reference in article

• 50

  BarndenLRShanZYStainesDRMarshall-GradisnikSFineganKIrelandTet al. Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome. NeuroImage Clin. (2018) 20:102–9. doi: 10.1016/j.nicl.2018.07.011

  • CrossRef
  • Google Scholar
  • View reference in article

• 51

  CockshellSJMathiasJL. Cognitive functioning in chronic fatigue syndrome: a meta-analysis. psychol Med. (2010) 40:1253–67. doi: 10.1017/S0033291709992054

  • CrossRef
  • Google Scholar
  • View reference in article

• 52

  ArizaME. Myalgic encephalomyelitis/chronic fatigue syndrome: the human herpesviruses are back! Biomolecules. (2021) 11. doi: 10.3390/biom11020185

  • CrossRef
  • Google Scholar
  • View reference in article

• 53

  PhebyDFHFriedmanKJMurovskaMZalewskiP. Turning a corner in ME/CFS research. Medicina (Kaunas) 57. (2021). doi: 10.3390/medicina57101012

  • CrossRef
  • Google Scholar
  • View reference in article

• 54

  JasonLABrownAClyneEBartgisLEvansMBrownM. Contrasting case definitions for chronic fatigue syndrome, Myalgic Encephalomyelitis/chronic fatigue syndrome and myalgic encephalomyelitis. Eval Health Prof. (2012) 35:280–304. doi: 10.1177/0163278711424281

  • CrossRef
  • Google Scholar
  • View reference in article

• 55

  BellDS. The doctor’s guide to chronic fatigue syndrome: understanding, treating, and living with Cfids. (Boston, Massachusetts: Da Capo Press) (1994).

  • Google Scholar
  • View reference in article

• 56

  DibbleJJMcGrathSJPontingCP. Genetic risk factors of ME/CFS: a critical review. Hum Mol Genet 29. (2020) 29, R117–r124. doi: 10.1093/hmg/ddaa169

  • CrossRef
  • Google Scholar
  • View reference in article

• 57

  NewberryFHsiehSYWilemanTCardingSR. Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome? Clin Sci (Lond). (2018) 132:523–42. doi: 10.1042/CS20171330

  • CrossRef
  • Google Scholar
  • View reference in article

• 58

  WirthKScheibenbogenC. A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors. Autoimmun Rev. (2020) 19:102527. doi: 10.1016/j.autrev.2020.102527

  • CrossRef
  • Google Scholar
  • View reference in article

• 59

  NaculLO’BoyleSPallaLNaculFEMudieKKingdonCCet al. How myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) progresses: the natural history of ME/CFS. Front Neurol. (2020) 11:826doi: 10.3389/fneur.2020.00826

  • CrossRef
  • Google Scholar
  • View reference in article

• 60

  ToogoodPLClauwDJPhadkeSHoffmanD. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from? Pharmacol Res. (2021) 165:105465. doi: 10.1016/j.phrs.2021.105465

  • CrossRef
  • Google Scholar
  • View reference in article

• 61

  ChuLValenciaIJGarvertDWMontoyaJG. Onset patterns and course of myalgic encephalomyelitis/chronic fatigue syndrome. Front Pediatr. (2019) 7:12. doi: 10.3389/fped.2019.00012

  • CrossRef
  • Google Scholar
  • View reference in article

• 62

  SalitIE. Precipitating factors for the chronic fatigue syndrome. J Psychiatr Res. (1997) 31:59–65. doi: 10.1016/S0022-3956(96)00050-7

  • CrossRef
  • Google Scholar
  • View reference in article

• 63

  TateWWalkerMSweetmanEHelliwellAPeppercornKEdgarCet al. Molecular mechanisms of neuroinflammation in ME/CFS and long COVID to sustain disease and promote relapses. Front Neurol. (2022) 13:877772. doi: 10.3389/fneur.2022.877772

  • CrossRef
  • Google Scholar
  • View reference in article

• 64

  KlimasNGBroderickGFletcherMA. Biomarkers for chronic fatigue. Brain Behav Immun. (2012) 26:1202–10. doi: 10.1016/j.bbi.2012.06.006

  • CrossRef
  • Google Scholar
  • View reference in article

• 65

  WalshCMZainalNZMiddletonSJPaykelES. A family history study of chronic fatigue syndrome. Psychiatr Genet. (2001) 11:123–8. doi: 10.1097/00041444-200109000-00003

  • CrossRef
  • Google Scholar
  • View reference in article

• 66

  AlbrightFLightKLightABatemanLCannon-AlbrightLA. Evidence for a heritable predisposition to Chronic Fatigue Syndrome. BMC Neurol. (2011) 11:62. doi: 10.1186/1471-2377-11-62

  • CrossRef
  • Google Scholar
  • View reference in article

• 67

  BuchwaldDHerrellRAshtonSBelcourtMSchmalingKSullivanPet al. A twin study of chronic fatigue. Psychosom Med. (2001) 63:936–43. doi: 10.1097/00006842-200111000-00012

  • CrossRef
  • Google Scholar
  • View reference in article

• 68

  UnderhillRO’GormanR. Prevalence of chronic fatigue syndrome and chronic fatigue within families of CFS patients. J Chronic Fatigue Syndrome. (2006) 13:3–13. doi: 10.1300/J092v13n01_02

  • CrossRef
  • Google Scholar
  • View reference in article

• 69

  PerezMJaundooRHiltonKDel AlamoAGemayelKKlimasNGet al. Genetic predisposition for immune system, hormone, and metabolic dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study. Front Pediatr. (2019) 7:206.doi: 10.3389/fped.2019.00206

  • CrossRef
  • Google Scholar
  • View reference in article

• 70

  MaherB. Personal genomes: The case of the missing heritability. Nature. (2008) 456:18–21. doi: 10.1038/456018a

  • CrossRef
  • Google Scholar
  • View reference in article

• 71

  LakhaniCMTierneyBTManraiAKYangJVisscherPMPatelCJ. Repurposing large health insurance claims data to estimate genetic and environmental contributions in 560 phenotypes. Nat Genet. (2019) 51:327–34. doi: 10.1038/s41588-018-0313-7

  • CrossRef
  • Google Scholar
  • View reference in article

• 72

  Canela-XandriORawlikKTenesaA. An atlas of genetic associations in UK Biobank. Nat Genet. (2018) 50:1593–9. doi: 10.1038/s41588-018-0248-z

  • CrossRef
  • Google Scholar
  • View reference in article

• 73

  SullivanPFEvengårdBJacksAPedersenNL. Twin analyses of chronic fatigue in a Swedish national sample. Psychol Med. (2005) 35:1327–36. doi: 10.1017/S0033291705005222

  • CrossRef
  • Google Scholar
  • View reference in article

• 74

  Carlo-StellaNBadulliCDe SilvestriABazzichiLMartinettiMLorussoLet al. A first study of cytokine genomic polymorphisms in CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles. Clin Exp Rheumatol. (2006) 24:179–82.

  • Google Scholar
  • View reference in article

• 75

  VangeelEVan Den EedeFHompesTIzziBDel FaveroJMoorkensGet al. Chronic fatigue syndrome and DNA hypomethylation of the glucocorticoid receptor gene promoter 1F region: associations with HPA axis hypofunction and childhood trauma. Psychosomatic Med 77. (2015). doi: 10.1097/PSY.0000000000000224

  • CrossRef
  • Google Scholar
  • View reference in article

• 76

  KashiAADavisRWPhairRD. The IDO metabolic trap hypothesis for the etiology of ME/CFS. Diagnostics (Basel) 9. (2019). doi: 10.3390/diagnostics9030082

  • CrossRef
  • Google Scholar
  • View reference in article

• 77

  MetzRDuhadawayJBKamasaniULaury-KleintopLMullerAJPrendergastGC. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. (2007) 67:7082–7. doi: 10.1158/0008-5472.CAN-07-1872

  • CrossRef
  • Google Scholar
  • View reference in article

• 78

  SommerfeldtLPortillaHJacobsenLGjerstadJWyllerVB. Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome. Acta Paediatrica. (2011) 100:293–8. doi: 10.1111/j.1651-2227.2010.02072.x

  • CrossRef
  • Google Scholar
  • View reference in article

• 79

  EisenachJHWittwerED. β-Adrenoceptor gene variation and intermediate physiological traits: prediction of distant phenotype. Exp Physiol. (2010) 95:757–64. doi: 10.1113/expphysiol.2009.048330

  • CrossRef
  • Google Scholar
  • View reference in article

• 80

  WittwerEDLiuZWarnerNDSchroederDRNadeauAMAllenARet al. Beta-1 and beta-2 adrenergic receptor polymorphism and association with cardiovascular response to orthostatic screening. Autonomic Neurosci. (2011) 164:89–95. doi: 10.1016/j.autneu.2011.07.004

  • CrossRef
  • Google Scholar
  • View reference in article

• 81

  SnyderEMBeckKCDietzNMEisenachJHJoynerMJTurnerSTet al. Arg16Gly polymorphism of the beta2-adrenergic receptor is associated with differences in cardiovascular function at rest and during exercise in humans. J Physiol. (2006) 571:121–30. doi: 10.1113/jphysiol.2005.098558

  • CrossRef
  • Google Scholar
  • View reference in article

• 82

  TanigawaYLiJJustesenJMHornHAguirreMDeBoeverCet al. Components of genetic associations across 2,138 phenotypes in the UK Biobank highlight adipocyte biology. Nat Commun. (2019) 10:4064. doi: 10.1038/s41467-019-11953-9

  • CrossRef
  • Google Scholar
  • View reference in article

• 83

  LiYRLiJZhaoSDBradfieldJPMentchFDMaggadottirSMet al. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat Med. (2015) 21:1018–27. doi: 10.1038/nm.3933

  • CrossRef
  • Google Scholar
  • View reference in article

• 84

  FlugeØRisaKLundeSAlmeKRekelandIGSapkotaDet al. B-lymphocyte depletion in myalgic encephalopathy/chronic fatigue syndrome. An open-label phase II study with rituximab maintenance treatment. PloS One. (2015) 10:e0129898. doi: 10.1371/journal.pone.0129898

  • CrossRef
  • Google Scholar
  • View reference in article

• 85

  BlombergJGottfriesCGElfaitouriARizwanMRosénA. Infection elicited autoimmunity and myalgic encephalomyelitis/chronic fatigue syndrome: an explanatory model. Front Immunol. (2018) 9:229. doi: 10.3389/fimmu.2018.00229

  • CrossRef
  • Google Scholar
  • View reference in article

• 86

  MeyerDC.A.VRBitarelloBDC.B.DYNunesK. A genomic perspective on HLA evolution. Immunogenetics. (2018) 70:5–27. doi: 10.1007/s00251-017-1017-3

  • CrossRef
  • Google Scholar
  • View reference in article

• 87

  YasukochiYSattaY. A human-specific allelic group of the MHC DRB1 gene in primates. J Physiol Anthropol. (2014) 33:14. doi: 10.1186/1880-6805-33-14

  • CrossRef
  • Google Scholar
  • View reference in article

• 88

  SmithJFritzELKerrJRCleareAJWesselySMatteyDL. Association of chronic fatigue syndrome with human leucocyte antigen class II alleles. J Clin Pathol. (2005) 58:860–3. doi: 10.1136/jcp.2004.022681

  • CrossRef
  • Google Scholar
  • View reference in article

• 89

  LandeAFlugeØStrandEBFlåmSTSosaDDMellaOet al. Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Sci Rep. (2020) 10:5267. doi: 10.1038/s41598-020-62157-x

  • CrossRef
  • Google Scholar
  • View reference in article

• 90

  Ruiz-PablosMPaivaBMontero-MateoRGarciaNZabaletaA. Epstein-barr virus and the origin of myalgic encephalomyelitis or chronic fatigue syndrome. Front Immunol. (2021) 12:656797. doi: 10.3389/fimmu.2021.656797

  • CrossRef
  • Google Scholar
  • View reference in article

• 91

  SchoemanEMvan der WesthuisenFHErasmusEvan DykEKnowlesCVAl-AliSet al. Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome. BMC Med Genet. (2017) 18:29. doi: 10.1186/s12881-017-0387-6

  • CrossRef
  • Google Scholar
  • View reference in article

• 92

  Billing-RossPGermainAYeKKeinanAGuZHansonMR. Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. (2016) 14:19. doi: 10.1186/s12967-016-0771-6

  • CrossRef
  • Google Scholar
  • View reference in article

• 93

  VenterMTomasCPienaarISStrassheimVErasmusENgWFet al. MtDNA population variation in Myalgic encephalomyelitis/Chronic fatigue syndrome in two populations: a study of mildly deleterious variants. Sci Rep. (2019) 9:2914. doi: 10.1038/s41598-019-39060-1

  • CrossRef
  • Google Scholar

• 94

  Ortega-HernandezODShoenfeldY. Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence? Ann N Y Acad Sci. (2009) 1173:600–9. doi: 10.1111/j.1749-6632.2009.04799.x

  • CrossRef
  • Google Scholar

• 95

  ArnettSVAllevaLMKorossy-HorwoodRClarkIA. Chronic fatigue syndrome–a neuroimmunological model. Med Hypotheses. (2011) 77:77–83. doi: 10.1016/j.mehy.2011.03.030

  • CrossRef
  • Google Scholar

• 96

  LacerdaEMGeraghtyKKingdonCCPallaLNaculL. A logistic regression analysis of risk factors in ME/CFS pathogenesis. BMC Neurol. (2019) 19:275. doi: 10.1186/s12883-019-1468-2

  • CrossRef
  • Google Scholar

• 97

  PrinsJBvan der MeerJWBleijenbergG. Chronic fatigue syndrome. Lancet. (2006) 367:346–55. doi: 10.1016/S0140-6736(06)68073-2

  • CrossRef
  • Google Scholar

• 98

  NaessHSundalEMyhrKMNylandHI. Postinfectious and chronic fatigue syndromes: clinical experience from a tertiary-referral centre in Norway. In Vivo. (2010) 24:185–8.

  • Google Scholar

• 99

  RasaSNora-KrukleZHenningNEliassenEShikovaEHarrerTet al. Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Transl Med. (2018) 16:268. doi: 10.1186/s12967-018-1644-y

  • CrossRef
  • Google Scholar

• 100

  SospedraMMartinR. Immunology of multiple sclerosis. Annu Rev Immunol. (2005) 23:683–747. doi: 10.1146/annurev.immunol.23.021704.115707

  • CrossRef
  • Google Scholar

• 101

  WekerleH. Epstein-Barr virus sparks brain autoimmunity in multiple sclerosis. Nature. (2022) 603:230–2. doi: 10.1038/d41586-022-00382-2

  • CrossRef
  • Google Scholar

• 102

  MontoyaJGKogelnikAMBhangooMLunnMRFlamandLMerrihewLEet al. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol (2013) 85:2101–9.

  • Google Scholar

• 103

  KatzBZShiraishiYMearsCJBinnsHJTaylorR. Chronic fatigue syndrome after infectious mononucleosis in adolescents. Pediatrics. (2009) 124:189–93. doi: 10.1542/peds.2008-1879

  • CrossRef
  • Google Scholar

• 104

  ChiaJKChiaAY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol (2008) 61:43–8.

  • Google Scholar

• 105

  KerrJRGoughJRichardsSCMainJEnlanderDMcCrearyMet al. Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Gen Virol (2010) 91:893–7.

  • Google Scholar

• 106

  JacobsonSKDalyJSThorneGMMcIntoshK. Chronic parvovirus B19 infection resulting in chronic fatigue syndrome: case history andf review. Clin Infect Dis (1997) 24:1048–51.

  • Google Scholar

• 107

  ChiaJChiaAVoellerMLeeTChangR. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence. J Clin Pathol. (2010) 63:165–8. doi: 10.1136/jcp.2009.070466

  • CrossRef
  • Google Scholar

• 108

  ChiaJK. The role of enterovirus in chronic fatigue syndrome. J Clin Pathol (2005) 58:1126–32.

  • Google Scholar

• 109

  HickieIDavenportTWakefieldDVollmer-ConnaUCameronBVernonSDet al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. Bmj. (2006) 333:575. doi: 10.1136/bmj.38933.585764.AE

  • CrossRef
  • Google Scholar

• 110

  PerrinRRisteLHannMWaltherAMukherjeeAHealdA. Into the looking glass: Post-viral syndrome post COVID-19. Med Hypotheses (2020) 144:110055.

  • Google Scholar

• 111

  KomaroffALBatemanL. Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Front Med (Lausanne) (2020) 7:606824.

  • Google Scholar

• 112

  ChiaJKChiaLY. Chronic Chlamydia pneumoniae infection: a treatable cause of chronic fatigue syndrome. Clin Infect Dis (1999) 29:452–3.

  • Google Scholar

• 113

  ZhangLGoughJChristmasDMatteyDLRichardsSCMainJet al. Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis. J Clin Pathol. (2010) 63:156–64. doi: 10.1136/jcp.2009.072561

  • CrossRef
  • Google Scholar

• 114

  KomaroffAL. Is human herpesvirus-6 a trigger for chronic fatigue syndrome? J Clin Virol (2006) 37 Suppl 1:S39–46.

  • Google Scholar

• 115

  WrayBGaughfCChandlerFJr.BerrySLathamJWoodLet al. Detection of Epstein-Barr virus and cytomegalovirus in patients with chronic fatigue. Ann Allergy (1993) 71:223–6.

  • Google Scholar

• 116

  JonesJFRayCGMinnichLLHicksMJKiblerRLucasDO. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med (1985) 102:1–7.

  • Google Scholar

• 117

  SejvarJJCurnsATWelburgLJonesJFLundgrenLMCapuronLet al. Neurocognitive and functional outcomes in persons recovering from West Nile virus illness. J Neuropsychol (2008) 2:477–99.

  • Google Scholar

• 118

  EvengårdBGränsHWahlundENordCE. Increased number of Candida albicans in the faecal microflora of chronic fatigue syndrome patients during the acute phase of illness. Scand J Gastroenterol (2007) 42:1514–5.

  • Google Scholar

• 119

  MoldofskyHPatcaiJ. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol (2011) 11:37.

  • Google Scholar

• 120

  EpsteinLWongKKKallenAJUyekiTM. Post-Ebola Signs and Symptoms in U. S. Survivors. N Engl J Med (2015) 373:2484–6.

  • Google Scholar

• 121

  SeetRCQuekAMLimEC. Post-infectious fatigue syndrome in dengue infection. J Clin Virol (2007) 38:1–6.

  • Google Scholar

• 122

  SalitIE. Sporadic postinfectious neuromyasthenia. Cmaj (1985) 133:659–63.

  • Google Scholar

• 123

  MørchKHanevikKRivenesACBødtkerJENæssHStubhaugBet al. Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course. BMC Gastroenterol (2013) 13:28.

  • Google Scholar

• 124

  BeqajSHLernerAMFitzgeraldJT. Immunoassay with cytomegalovirus early antigens from gene products p52 and CM2 (UL44 and UL57) detects active infection in patients with chronic fatigue syndrome. J Clin Pathol (2008) 61:623–6.

  • Google Scholar

• 125

  LamMHWingYKYuMWLeungCMMaRCKongAPet al. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up. Arch Intern Med (2009) 169:2142–7.

  • Google Scholar

• 126

  SigalLH. Summary of the first 100 patients seen at a lyme disease referral center. Am J Med (1990) 88:577–81.

  • Google Scholar

• 127

  LiuZHollmannCKalanidhiSGrotheyAKeatingSMena-PalomoIet al. Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID. medRxiv. (2023). doi: 10.1101/2023.06.23.23291827

  • CrossRef
  • Google Scholar

• 128

  BankoAMiljanovicDCirkovicA. Systematic review with meta-analysis of active herpesvirus infections in patients with COVID-19: Old players on the new field. Int J Infect Dis. (2023) 130:108–25. doi: 10.1016/j.ijid.2023.01.036

  • CrossRef
  • Google Scholar

• 129

  HagemeierSRBarlowEAKlemanAAKenneySC. The Epstein-Barr virus BRRF1 protein, Na, induces lytic infection in a TRAF2- and p53-dependent manner. J Virol. (2011) 85:4318–29. doi: 10.1128/JVI.01856-10

  • CrossRef
  • Google Scholar

• 130

  HalpinPWilliamsMVKlimasNGFletcherMABarnesZArizaME. Myalgic encephalomyelitis/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesviruses-encoded dUTPase: Implications in disease pathophysiology. J Med Virol. (2017) 89:1636–45. doi: 10.1002/jmv.24810

  • CrossRef
  • Google Scholar

• 131

  LernerAMArizaMEWilliamsMJasonLBeqajSFitzgeraldJTet al. Antibody to Epstein-Barr virus deoxyuridine triphosphate nucleotidohydrolase and deoxyribonucleotide polymerase in a chronic fatigue syndrome subset. PloS One. (2012) 7:e47891. doi: 10.1371/journal.pone.0047891

  • CrossRef
  • Google Scholar

• 132

  ArizaMERivaillerPGlaserRChenMWilliamsMV. Epstein-Barr virus encoded dUTPase containing exosomes modulate innate and adaptive immune responses in human dendritic cells and peripheral blood mononuclear cells. PloS One. (2013) 8:e69827. doi: 10.1371/journal.pone.0069827

  • CrossRef
  • Google Scholar

• 133

  ArizaMEGlaserRWilliamsMV. Human herpesviruses-encoded dUTPases: a family of proteins that modulate dendritic cell function and innate immunity. Front Microbiol. (2014) 5:504. doi: 10.3389/fmicb.2014.00504

  • CrossRef
  • Google Scholar

• 134

  MurataTOkunoYSatoYWatanabeTKimuraH. Oncogenesis of CAEBV revealed: Intragenic deletions in the viral genome and leaky expression of lytic genes. Rev Med Virol. (2020) 30:e2095. doi: 10.1002/rmv.2095

  • CrossRef
  • Google Scholar

• 135

  OkunoYMurataTSatoYMuramatsuHItoYWatanabeTet al. Defective Epstein-Barr virus in chronic active infection and haematological Malignancy. Nat Microbiol. (2019) 4:404–13. doi: 10.1038/s41564-018-0334-0

  • CrossRef
  • Google Scholar

• 136

  LaichalkLLThorley-LawsonDA. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol. (2005) 79:1296–307. doi: 10.1128/JVI.79.2.1296-1307.2005

  • CrossRef
  • Google Scholar

• 137

  Williams PhDMCoxBLafuse PhDWArizaME. Epstein-barr virus dUTPase induces neuroinflammatory mediators: implications for myalgic encephalomyelitis/chronic fatigue syndrome. Clin Ther. (2019) 41:848–63. doi: 10.1016/j.clinthera.2019.04.009

  • CrossRef
  • Google Scholar

• 138

  BuchwaldDAshleyRLPearlmanTKithPKomaroffAL. Viral serologies in patients with chronic fatigue and chronic fatigue syndrome. J Med Virol. (1996) 50:25–30. doi: 10.1002/(ISSN)1096-9071

  • CrossRef
  • Google Scholar

• 139

  BuchwaldDSullivanJLKomaroffAL. Frequency of ‘chronic active Epstein-Barr virus infection’ in a general medical practice. Jama. (1987) 257:2303–7. doi: 10.1001/jama.257.17.2303

  • CrossRef
  • Google Scholar

• 140

  DuBoisRESeeleyJKBrusISakamotoKBallowMHaradaSet al. Chronic mononucleosis syndrome. South Med J. (1984) 77:1376–82. doi: 10.1097/00007611-198411000-00007

  • CrossRef
  • Google Scholar

• 141

  TobiMMoragARavidZChowersIFeldman-WeissVMichaeliYet al. Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet. (1982) 1:61–4. doi: 10.1016/S0140-6736(82)90210-0

  • CrossRef
  • Google Scholar

• 142

  HolmesGPKaplanJEStewartJAHuntBPinskyPFSchonbergerLB. A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr Virus cause? JAMA. (1987) 257:2297–302. doi: 10.1001/jama.257.17.2297

  • CrossRef
  • Google Scholar

• 143

  HellingerWCSmithTFVan ScoyRESpitzerPGForgacsPEdsonRS. Chronic fatigue syndrome and the diagnostic utility of antibody to Epstein-Barr virus early antigen. Jama. (1988) 260:971–3. doi: 10.1001/jama.260.7.971

  • CrossRef
  • Google Scholar

• 144

  StrausSEDaleJKTobiMLawleyTPrebleOBlaeseRMet al. Acyclovir treatment of the chronic fatigue syndrome Lack of efficacy in a placebo-controlled trial. . N Engl J Med. (1988) 319:1692–8. doi: 10.1056/NEJM198812293192602

  • CrossRef
  • Google Scholar

• 145

  GoldDBowdenRSixbeyJRiggsRKatonWJAshleyRet al. Chronic fatigue. A prospective clinical and virologic study. Jama. (1990) 264:48–53. doi: 10.1001/jama.264.1.48

  • CrossRef
  • Google Scholar

• 146

  LevinePHJacobsonSPocinkiAGCheneyPPetersonDConnellyRRet al. Clinical, epidemiologic, and virologic studies in four clusters of the chronic fatigue syndrome. Arch Intern Med. (1992) 152:1611–6. doi: 10.1001/archinte.152.8.1611

  • CrossRef
  • Google Scholar

• 147

  CameronBFlamandLJuwanaHMiddeldorpJNaingZRawlinsonWet al. Serological and virological investigation of the role of the herpesviruses EBV, CMV and HHV-6 in post-infective fatigue syndrome. J Med Virol. (2010) 82:1684–8. doi: 10.1002/jmv.21873

  • CrossRef
  • Google Scholar

• 148

  LoebelMEckeyMSotznyFHahnEBauerSGrabowskiPet al. Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray. PloS One. (2017) 12:e0179124. doi: 10.1371/journal.pone.0179124

  • CrossRef
  • Google Scholar

• 149

  BlombergJRizwanMBöhlin-WienerAElfaitouriAJulinPZachrissonOet al. Antibodies to human herpesviruses in myalgic encephalomyelitis/chronic fatigue syndrome patients. Front Immunol. (2019) 10:1946. doi: 10.3389/fimmu.2019.01946

  • CrossRef
  • Google Scholar

• 150

  SotoNEStrausSE. Chronic fatigue syndrome and herpesviruses: the fading evidence. Herpes. (2000) 7:46–50.

  • Google Scholar

• 151

  GärtnerBCFischingerJMRoemerKMakMFleurentBMueller-LantzschN. Evaluation of a recombinant line blot for diagnosis of Epstein-Barr Virus compared with ELISA, using immunofluorescence as reference method. J Virol Methods. (2001) 93:89–96. doi: 10.1016/S0166-0934(00)00301-3

  • CrossRef
  • Google Scholar

• 152

  TahmazNSoutarACherrieJW. Chronic fatigue and organophosphate pesticides in sheep farming: a retrospective study amongst people reporting to a UK pharmacovigilance scheme. Ann Occup Hyg. (2003) 47:261–7. doi: 10.1093/annhyg/meg042

  • CrossRef
  • Google Scholar

• 153

  BehanPO. Chronic fatigue syndrome as a delayed reaction to chronic low-dose organophosphate exposure. J Nutr Environ Med. (1996) 6:341–50. doi: 10.3109/13590849609007262

  • CrossRef
  • Google Scholar

• 154

  PaciniSFioreMGMagheriniSMorucciGBrancaJJGulisanoMet al. Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Med Hypotheses. (2012) 79:403–7. doi: 10.1016/j.mehy.2012.06.007

  • CrossRef
  • Google Scholar

• 155

  LópezEArceCOset-GasqueMJCañadasSGonzálezMP. Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture. Free Radic Biol Med. (2006) 40:940–51. doi: 10.1016/j.freeradbiomed.2005.10.062

  • CrossRef
  • Google Scholar

• 156

  de LangeFPKalkmanJSBleijenbergGHagoortPvan der MeerJWMToniI. Gray matter volume reduction in the chronic fatigue syndrome. NeuroImage. (2005) 26:777–81. doi: 10.1016/j.neuroimage.2005.02.037

  • CrossRef
  • Google Scholar

• 157

  HartRPRoseCSHamerRM. Neuropsychological effects of occupational exposure to cadmium. J Clin Exp Neuropsychol. (1989) 11:933–43. doi: 10.1080/01688638908400946

  • CrossRef
  • Google Scholar

• 158

  BiswalBKunwarPNatelsonBH. Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling. J Neurol Sci. (2011) 301:9–11. doi: 10.1016/j.jns.2010.11.018

  • CrossRef
  • Google Scholar

• 159

  YoshiuchiKFarkasJNatelsonBH. Patients with chronic fatigue syndrome have reduced absolute cortical blood flow. Clin Physiol Funct Imaging. (2006) 26:83–6. doi: 10.1111/j.1475-097X.2006.00649.x

  • CrossRef
  • Google Scholar

• 160

  PaciniSPunziTMorucciGGulisanoMRuggieroM. A paradox of cadmium: a carcinogen that impairs the capability of human breast cancer cells to induce angiogenesis. J Environ Pathol Toxicol Oncol. (2009) 28:85–8. doi: 10.1615/JEnvironPatholToxicolOncol.v28.i1

  • CrossRef
  • Google Scholar

• 161

  StejskalVDDanersundALindvallAHudecekRNordmanVYaqobAet al. Metal-specific lymphocytes: biomarkers of sensitivity in man. Neuro Endocrinol Lett. (1999) 20:289–98.

  • Google Scholar

• 162

  Valentine-ThonEMüllerKGuzziGKreiselSOhnsorgePSandkampM. LTT-MELISA is clinically relevant for detecting and monitoring metal sensitivity. Neuro Endocrinol Lett. (2006) 27 Suppl 1:17–24.

  • Google Scholar

• 163

  GherardiRKCrépeauxGAuthierF-J. Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system. Autoimmun Rev. (2019) 18:691–705. doi: 10.1016/j.autrev.2019.05.006

  • CrossRef
  • Google Scholar

• 164

  SleighKMMarraFHStiverHG. Influenza vaccination: is it appropriate in chronic fatigue syndrome? Am J Respir Med. (2002) 1:3–9. doi: 10.1007/BF03257157

  • CrossRef
  • Google Scholar

• 165

  ManyshevaKShermanMZhukovaNKopishinskaiaS. Myalgic encephalomyelitis/chronic fatigue syndrome: first described complication after gam-COVID-vac vaccine. Psychiatr Danub. (2022) 34:189–90.

  • Google Scholar

• 166

  GherardiRK. [Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome]. Rev Neurol (Paris). (2003) 159:162–4.

  • Google Scholar

• 167

  ShoenfeldYAgmon-LevinN. ‘ASIA’ - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. (2011) 36:4–8. doi: 10.1016/j.jaut.2010.07.003

  • CrossRef
  • Google Scholar

• 168

  GherardiRKCoquetMCherinPBelecLMorettoPDreyfusPAet al. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminum hydroxide in muscle. Brain. (2001) 124:1821–31. doi: 10.1093/brain/124.9.1821

  • CrossRef
  • Google Scholar

• 169

  FeiringBLaakeIBakkenIJGreve-IsdahlMWyllerVBHåbergSEet al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway. Vaccine. (2017) 35:4203–12. doi: 10.1016/j.vaccine.2017.06.031

  • CrossRef
  • Google Scholar

• 170

  PrinsenHde VriesIJMTorensmaRPotsJMMulderSFvan HerpenCMLet al. Humoral and cellular immune responses after influenza vaccination in patients with chronic fatigue syndrome. BMC Immunol. (2012) 13:71. doi: 10.1186/1471-2172-13-71

  • CrossRef
  • Google Scholar

• 171

  SleighKMDanforthDGHallRTFlemingJAStiverHG. Double-blind, randomised study of the effects of influenza vaccination on the specific antibody response and clinical course of patients with chronic fatigue syndrome. Can J Infect Dis. (2000) 11:267–73. doi: 10.1155/2000/602862

  • CrossRef
  • Google Scholar

• 172

  GolombBAKoslikHJReddAJ. Fluoroquinolone-induced serious, persistent, multisymptom adverse effects. BMJ Case Rep 2015. (2015). doi: 10.1136/bcr-2015-209821

  • CrossRef
  • Google Scholar

• 173

  BalfourJAWisemanLR. Moxifloxacin. Drugs. (1999) 57:363–73. doi: 10.2165/00003495-199957030-00007

  • CrossRef
  • Google Scholar

• 174

  LipskyBADorrMBMagnerDJTalbotGH. Safety profile of sparfloxacin, a new fluoroquinolone antibiotic. Clin Ther. (1999) 21:148–59. doi: 10.1016/S0149-2918(00)88275-2

  • CrossRef
  • Google Scholar

• 175

  WimerSMSchoonoverLGarrisonMW. Levofloxacin: a therapeutic review. Clin Ther. (1998) 20:1049–70. doi: 10.1016/S0149-2918(98)80104-5

  • CrossRef
  • Google Scholar

• 176

  KaleagasiogluFOlcayE. Fluoroquinolone-induced tendinopathy: etiology and preventive measures. Tohoku J Exp Med. (2012) 226:251–8. doi: 10.1620/tjem.226.251

  • CrossRef
  • Google Scholar

• 177

  TsaiWCYangYM. Fluoroquinolone-associated tendinopathy. Chang Gung Med J. (2011) 34:461–7.

  • Google Scholar

• 178

  SendzikJShakibaeiMSchäfer-KortingMLodeHStahlmannR. Synergistic effects of dexamethasone and quinolones on human-derived tendon cells. Int J Antimicrob Agents. (2010) 35:366–74. doi: 10.1016/j.ijantimicag.2009.10.009

  • CrossRef
  • Google Scholar

• 179

  KimGK. The risk of fluoroquinolone-induced tendinopathy and tendon rupture: what does the clinician need to know? J Clin Aesthet Dermatol. (2010) 3:49–54.

  • Google Scholar

• 180

  LowesDAWallaceCMurphyMPWebsterNRGalleyHF. The mitochondria targeted antioxidant MitoQ protects against fluoroquinolone-induced oxidative stress and mitochondrial membrane damage in human Achilles tendon cells. Free Radic Res. (2009) 43:323–8. doi: 10.1080/10715760902736275

  • CrossRef
  • Google Scholar

• 181

  KeelMTrentzO. Pathophysiology of polytrauma. Injury. (2005) 36:691–709. doi: 10.1016/j.injury.2004.12.037

  • CrossRef
  • Google Scholar

• 182

  MorrisGBerkMGaleckiPMaesM. The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs). Mol Neurobiol. (2014) 49:741–56. doi: 10.1007/s12035-013-8553-0

  • CrossRef
  • Google Scholar

• 183

  StanculescuDSepúlvedaNLimCLBergquistJ. Lessons from heat stroke for understanding myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. (2021) 12:789784. doi: 10.3389/fneur.2021.789784

  • CrossRef
  • Google Scholar

• 184

  FlugeØMellaOBrulandORisaKDyrstadSEAlmeKet al. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. (2016) 1:e89376. doi: 10.1172/jci.insight.89376

  • CrossRef
  • Google Scholar

• 185

  HoelFHoelAPettersenIKRekelandIGRisaKAlmeKet al. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight 6. (2021). doi: 10.1172/jci.insight.149217

  • CrossRef
  • Google Scholar

• 186

  GermainARuppertDLevineSMHansonMR. Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol Biosyst. (2017) 13:371–9. doi: 10.1039/C6MB00600K

  • CrossRef
  • Google Scholar

• 187

  ArmstrongCWMcGregorNRLewisDPButtHLGooleyPR. Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients. Metabolomics. (2015) 11:1626–39. doi: 10.1007/s11306-015-0816-5

  • CrossRef
  • Google Scholar

• 188

  KennedyGSpenceVAMcLarenMHillAUnderwoodCBelchJJ. Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radic Biol Med. (2005) 39:584–9. doi: 10.1016/j.freeradbiomed.2005.04.020

  • CrossRef
  • Google Scholar

• 189

  SteinsvikEKHauskenTFlugeØMellaOGiljaOH. Gastric dysmotility and gastrointestinal symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. Scandinavian J Gastroenterol. (2023) 58:718–25. doi: 10.1080/00365521.2023.2173533

  • CrossRef
  • Google Scholar

• 190

  LakhanSEKirchgessnerA. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). (2010) 7:79. doi: 10.1186/1743-7075-7-79

  • CrossRef
  • Google Scholar

• 191

  GiloteauxLGoodrichJKWaltersWALevineSMLeyREHansonMR. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. (2016) 4:30. doi: 10.1186/s40168-016-0171-4

  • CrossRef
  • Google Scholar

• 192

  LupoGFDRocchettiGLuciniLLorussoLManaraEBertelliMet al. Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelits (CFS/ME). Sci Rep. (2021) 11:7043. doi: 10.1038/s41598-021-86425-6

  • CrossRef
  • Google Scholar

• 193

  ProalAMarshallT. Myalgic encephalomyelitis/chronic fatigue syndrome in the era of the human microbiome: persistent pathogens drive chronic symptoms by interfering with host metabolism, gene expression, and immunity. Front Pediatr. (2018) 6:373. doi: 10.3389/fped.2018.00373

  • CrossRef
  • Google Scholar

• 194

  Nagy-SzakalDWilliamsBLMishraNCheXLeeBBatemanLet al. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. (2017) 5:44. doi: 10.1186/s40168-017-0261-y

  • CrossRef
  • Google Scholar

• 195

  MachielsKJoossensMSabinoJDe PreterVArijsIEeckhautVet al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. (2014) 63:1275–83. doi: 10.1136/gutjnl-2013-304833

  • CrossRef
  • Google Scholar

• 196

  SegainJPRaingeard de la BlétièreDBourreilleALerayVGervoisNRosalesCet al. Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn’s disease. Gut. (2000) 47:397–403. doi: 10.1136/gut.47.3.397

  • CrossRef
  • Google Scholar

• 197

  Ríos-CoviánDRuas-MadiedoPMargollesAGueimondeMde Los Reyes-GavilánCGSalazarN. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. (2016) 7:185. doi: 10.3389/fmicb.2016.00185

  • CrossRef
  • Google Scholar

• 198

  ArmstrongCWMcGregorNRLewisDPButtHLGooleyPR. The association of fecal microbiota and fecal, blood serum and urine metabolites in myalgic encephalomyelitis/chronic fatigue syndrome. Metabolomics. (2017) 13:1–13. doi: 10.1007/s11306-016-1145-z

  • CrossRef
  • Google Scholar

• 199

  RizzattiGLopetusoLRGibiinoGBindaCGasbarriniA. Proteobacteria: A common factor in human diseases. BioMed Res Int. (2017) 2017:9351507. doi: 10.1155/2017/9351507

  • CrossRef
  • Google Scholar

• 200

  CarrollIMRingel-KulkaTSiddleJPRingelY. Alterations in composition and diversity of the intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil. (2012) 24:521–30.e248. doi: 10.1111/j.1365-2982.2012.01891.x

  • CrossRef
  • Google Scholar

• 201

  KomaroffALLipkinWI. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome. Trends Mol Med. (2021) 27:895–906. doi: 10.1016/j.molmed.2021.06.002

  • CrossRef
  • Google Scholar

• 202

  ErcoliGFernandesVEChungWYWanfordJJThomsonSBaylissCDet al. Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia. Nat Microbiol. (2018) 3:600–10. doi: 10.1038/s41564-018-0147-1

  • CrossRef
  • Google Scholar

• 203

  BaldelliVScaldaferriFPutignaniLDel ChiericoF. The role of enterobacteriaceae in gut microbiota dysbiosis in inflammatory bowel diseases. Microorganisms 9. (2021). doi: 10.3390/microorganisms9040697

  • CrossRef
  • Google Scholar

• 204

  ScalesBSDicksonRPHuffnagleGB. A tale of two sites: how inflammation can reshape the microbiomes of the gut and lungs. J Leukoc Biol. (2016) 100:943–50. doi: 10.1189/jlb.3MR0316-106R

  • CrossRef
  • Google Scholar

• 205

  MaesMMihaylovaILeunisJC. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord. (2007) 99:237–40. doi: 10.1016/j.jad.2006.08.021

  • CrossRef
  • Google Scholar

• 206

  PageMJKellDBPretoriusE. The role of lipopolysaccharide-induced cell signalling in chronic inflammation. Chronic Stress (Thousand Oaks). (2022) 6:24705470221076390. doi: 10.1177/24705470221076390

  • CrossRef
  • Google Scholar

• 207

  TanYKaganJC. A cross-disciplinary perspective on the innate immune responses to bacterial lipopolysaccharide. Mol Cell. (2014) 54:212–23. doi: 10.1016/j.molcel.2014.03.012

  • CrossRef
  • Google Scholar

• 208

  PłóciennikowskaAHromada-JudyckaABorzęckaKKwiatkowskaK. Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling. Cell Mol Life Sci. (2015) 72:557–81. doi: 10.1007/s00018-014-1762-5

  • CrossRef
  • Google Scholar

• 209

  RutherfordNJSacinoANBrooksMCeballos-DiazCLaddTBHowardJKet al. Studies of lipopolysaccharide effects on the induction of α-synuclein pathology by exogenous fibrils in transgenic mice. Mol Neurodegener. (2015) 10:32. doi: 10.1186/s13024-015-0029-4

  • CrossRef
  • Google Scholar

• 210

  KellDBPretoriusE. On the translocation of bacteria and their lipopolysaccharides between blood and peripheral locations in chronic, inflammatory diseases: the central roles of LPS and LPS-induced cell death. Integr Biol (Camb). (2015) 7:1339–77. doi: 10.1039/c5ib00158g

  • CrossRef
  • Google Scholar

• 211

  LiuMBingG. Lipopolysaccharide animal models for Parkinson’s disease. Parkinsons Dis. (2011) 2011:327089. doi: 10.4061/2011/327089

  • CrossRef
  • Google Scholar

• 212

  ZielenSTrischlerJSchubertR. Lipopolysaccharide challenge: immunological effects and safety in humans. Expert Rev Clin Immunol. (2015) 11:409–18. doi: 10.1586/1744666X.2015.1012158

  • CrossRef
  • Google Scholar

• 213

  FreyDJungSBrackmannFRichter-KrausMTrollmannR. Hypoxia potentiates LPS-mediated cytotoxicity of BV2 microglial cells in vitro by synergistic effects on glial cytokine and nitric oxide system. Neuropediatrics. (2015) 46:321–8. doi: 10.1055/s-00000041

  • CrossRef
  • Google Scholar

• 214

  HoshinoKTakeuchiOKawaiTSanjoHOgawaTTakedaYet al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol. (1999) 162:3749–52. doi: 10.4049/jimmunol.162.7.3749

  • CrossRef
  • Google Scholar

• 215

  FujimotoYShimoyamaASudaYFukaseK. Synthesis and immunomodulatory activities of Helicobacter pylori lipophilic terminus of lipopolysaccharide including lipid A. Carbohydr Res. (2012) 356:37–43. doi: 10.1016/j.carres.2012.03.013

  • CrossRef
  • Google Scholar

• 216

  MedzhitovR. Origin and physiological roles of inflammation. Nature. (2008) 454:428–35. doi: 10.1038/nature07201

  • CrossRef
  • Google Scholar

• 217

  RossolMHeineHMeuschUQuandtDKleinCSweetMJet al. LPS-induced cytokine production in human monocytes and macrophages. Crit Rev Immunol. (2011) 31:379–446. doi: 10.1615/CritRevImmunol.v31.i5

  • CrossRef
  • Google Scholar

• 218

  SavageCDLopez-CastejonGDenesABroughD. NLRP3-inflammasome activating DAMPs stimulate an inflammatory response in glia in the absence of priming which contributes to brain inflammation after injury. Front Immunol. (2012) 3:288. doi: 10.3389/fimmu.2012.00288

  • CrossRef
  • Google Scholar

• 219

  MaesMCouckeFLeunisJC. Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome. Neuro Endocrinol Lett. (2007) 28:739–44.

  • Google Scholar

• 220

  Paez-EspinoDEloe-FadroshEAPavlopoulosGAThomasADHuntemannMMikhailovaNet al. Uncovering earth’s virome. Nature. (2016) 536:425–30. doi: 10.1038/nature19094

  • CrossRef
  • Google Scholar

• 221

  De SordiLLourençoMDebarbieuxL. “I will survive”: A tale of bacteriophage-bacteria coevolution in the gut. Gut Microbes. (2019) 10:92–9. doi: 10.1080/19490976.2018.1474322

  • CrossRef
  • Google Scholar

• 222

  WagnerJMaksimovicJFarriesGSimWHBishopRFCameronDJet al. Bacteriophages in gut samples from pediatric Crohn’s disease patients: metagenomic analysis using 454 pyrosequencing. Inflammation Bowel Dis. (2013) 19:1598–608. doi: 10.1097/MIB.0b013e318292477c

  • CrossRef
  • Google Scholar

• 223

  Pérez-BrocalVGarcía-LópezRVázquez-CastellanosJFNosPBeltránBLatorreAet al. Study of the viral and microbial communities associated with Crohn’s disease: a metagenomic approach. Clin Transl Gastroenterol. (2013) 4:e36. doi: 10.1038/ctg.2013.9

  • CrossRef
  • Google Scholar

• 224

  WangWJovelJHalloranBWineEPattersonJFordGet al. Metagenomic analysis of microbiome in colon tissue from subjects with inflammatory bowel diseases reveals interplay of viruses and bacteria. Inflammation Bowel Dis. (2015) 21:1419–27. doi: 10.1097/MIB.0000000000000344

  • CrossRef
  • Google Scholar

• 225

  HornigMMontoyaJGKlimasNGLevineSFelsensteinDBatemanLet al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv 1. (2015). doi: 10.1126/sciadv.1400121

  • CrossRef
  • Google Scholar

• 226

  NaculLde BarrosBKingdonCCCliffJMClarkTGMudieKet al. Evidence of clinical pathology abnormalities in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) from an analytic cross-sectional study. Diagnostics (Basel) 9. (2019). doi: 10.3390/diagnostics9020041

  • CrossRef
  • Google Scholar

• 227

  LorussoLMikhaylovaSVCapelliEFerrariDNgongaGKRicevutiG. Immunological aspects of chronic fatigue syndrome. Autoimmun Rev. (2009) 8:287–91. doi: 10.1016/j.autrev.2008.08.003

  • CrossRef
  • Google Scholar

• 228

  HornigMGottschalkGPetersonDLKnoxKKSchultzAFEddyMLet al. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry. (2016) 21:261–9. doi: 10.1038/mp.2015.29

  • CrossRef
  • Google Scholar

• 229

  BroderickGFuiteJKreitzAVernonSDKlimasNFletcherMA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. (2010) 24:1209–17. doi: 10.1016/j.bbi.2010.04.012

  • CrossRef
  • Google Scholar

• 230

  KuratsuneH. [Overview of chronic fatigue syndrome focusing on prevalence and diagnostic criteria]. Nihon Rinsho. (2007) 65:983–90.

  • Google Scholar

• 231

  MontoyaJGHolmesTHAndersonJNMaeckerHTRosenberg-HassonYValenciaIJet al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U.S.A. (2017) 114:E7150–e7158. doi: 10.1073/pnas.1710519114

  • CrossRef
  • Google Scholar

• 232

  MoudgilKDChoubeyD. Cytokines in autoimmunity: role in induction, regulation, and treatment. J Interferon Cytokine Res. (2011) 31:695–703. doi: 10.1089/jir.2011.0065

  • CrossRef
  • Google Scholar

• 233

  McKinneyEFSmithKG. T cell exhaustion and immune-mediated disease-the potential for therapeutic exhaustion. Curr Opin Immunol. (2016) 43:74–80. doi: 10.1016/j.coi.2016.09.005

  • CrossRef
  • Google Scholar

• 234

  SenDRKaminskiJBarnitzRAKurachiMGerdemannUYatesKBet al. The epigenetic landscape of T cell exhaustion. Science. (2016) 354:1165–9. doi: 10.1126/science.aae0491

  • CrossRef
  • Google Scholar

• 235

  BlundellSRayKKBucklandMWhitePD. Chronic fatigue syndrome and circulating cytokines: A systematic review. Brain Behav Immun. (2015) 50:186–95. doi: 10.1016/j.bbi.2015.07.004

  • CrossRef
  • Google Scholar

• 236

  DinarelloCA. Biologic basis for interleukin-1 in disease. Blood (1996) 87:2095–147.

  • Google Scholar

• 237

  DinarelloCA. Anti-inflammatory agents: Present and future. Cell (2010) 140:935–50.

  • Google Scholar

• 238

  AlmehedKd'EliaHFBokarewaMCarlstenH. Role of resistin as a marker of inflammation in systemic lupus erythematosus. Arthritis Res Ther (2008) 10:R15.

  • Google Scholar

• 239

  HuangXYangZ. Resistin's, obesity and insulin resistance: the continuing disconnect between rodents and humans. J Endocrinol Invest (2016) 39:607–15.

  • Google Scholar

• 240

  IdrissHTNaismithJH. TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech (2000) 50:184–95.

  • Google Scholar

• 241

  LandiABroadhurstDVernonSDTyrrellDLHoughtonM. Reductions in circulating levels of IL-16, IL-7 and VEGF-a in myalgic encephalomyelitis/chronic fatigue syndrome. Cytokine (2016) 78:27–36.

  • Google Scholar

• 242

  MassaguéJ. TGFβ signalling in context. Nat Rev Mol Cell Biol (2012) 13:616–30.

  • Google Scholar

• 243

  MiyamotoHSauraRHaradaTDoitaMMizunoK. The role of cyclooxygenase-2 and inflammatory cytokines in pain induction of herniated lumbar intervertebral disc. Kobe J Med Sci (2000) 46:13–28.

  • Google Scholar

• 244

  ProcacciniCJirilloEMatareseG. Leptin as an immunomodulator. Mol Aspects Med (2012) 33:35–45.

  • Google Scholar

• 245

  ProcacciniCLa RoccaCCarboneFDe RosaVGalganiMMatareseG. Leptin as immune mediator: Interaction between neuroendocrine and immune system. Dev Comp Immunol (2017) 66:120–9.

  • Google Scholar

• 246

  SimonsMGordonEClaesson-WelshL. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol (2016) 17:611–25.

  • Google Scholar

• 247

  TanakaTNarazakiMKishimotoT. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol (2014) 6:a016295.

  • Google Scholar

• 248

  MuriJKopfM. Redox regulation of immunometabolism. Nat Rev Immunol. (2021) 21:363–81. doi: 10.1038/s41577-020-00478-8

  • CrossRef
  • Google Scholar

• 249

  MittalMSiddiquiMRTranKReddySPMalikAB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. (2014) 20:1126–67. doi: 10.1089/ars.2012.5149

  • CrossRef
  • Google Scholar

• 250

  BiswasSK. Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxid Med Cell Longev. (2016) 2016:5698931. doi: 10.1155/2016/5698931

  • CrossRef
  • Google Scholar

• 251

  PaulBDLemleMDKomaroffALSnyderSH. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U.S.A. (2021) 118. doi: 10.1073/pnas.2024358118

  • CrossRef
  • Google Scholar

• 252

  NijsJNeesAPaulLDe KooningMIckmansKMeeusMet al. Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. Exerc Immunol Rev. (2014) 20:94–116.

  • Google Scholar

• 253

  BrenuEWvan DrielMLStainesDRAshtonKJRamosSBKeaneJet al. Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Transl Med. (2011) 9:81. doi: 10.1186/1479-5876-9-81

  • CrossRef
  • Google Scholar

• 254

  MandaranoAHMayaJGiloteauxLPetersonDLMaynardMGottschalkCGet al. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations. J Clin Invest. (2020) 130:1491–505. doi: 10.1172/JCI132185

  • CrossRef
  • Google Scholar

• 255

  Cortes RiveraMMastronardiCSilva-AldanaCTArcos-BurgosMLidburyBA. Myalgic encephalomyelitis/chronic fatigue syndrome: A comprehensive review. Diagnostics (Basel). (2019) 9. doi: 10.3390/diagnostics9030091

  • CrossRef
  • Google Scholar

• 256

  KellDBPretoriusE. The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications. Biochem J. (2022) 479:1653–708. doi: 10.1042/BCJ20220154

  • CrossRef
  • Google Scholar

• 257

  MaesMKuberaMUytterhoevenMVrydagsNBosmansE. Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med. Sci. Monit. (2011) 17:Sc11–5

  • Google Scholar

• 258

  CoyleCHKaderKN. Mechanisms of H2O2-induced oxidative stress in endothelial cells exposed to physiologic shear stress. Asaio J (2007) 53:17–22.

  • Google Scholar

• 259

  KurupRKKurupPA. Hypothalamic digoxin, cerebral chemical dominance and myalgic encephalomyelitis. Int J Neurosci (2003) 113:683–701.

  • Google Scholar

• 260

  IndoHPYenHCNakanishiIMatsumotoKTamuraMNaganoYet al. A mitochondrial superoxide theory for oxidative stress diseases and aging. J Clin Biochem Nutr (2015) 56:1–7.

  • Google Scholar

• 261

  YounusH. Therapeutic potentials of superoxide dismutase. Int J Health Sci (Qassim) (2018) 12:88–93.

  • Google Scholar

• 262

  BrkicSTomicSMaricDNovakov MikicATurkulovV. Lipid peroxidation is elevated in female patients with chronic fatigue syndrome. Med Sci Monit (2010) 16:Cr628–32.

  • Google Scholar

• 263

  KeenoyBMMoorkensGVertommenJDe LeeuwI. Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome. Life Sci (2001) 68:2037–49.

  • Google Scholar

• 264

  VecchietJCipolloneFFalascaKMezzettiAPizzigalloEBucciarelliTet al. Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome. Neurosci Lett (2003) 335:151–4.

  • Google Scholar

• 265

  GawełSWardasMNiedworokEWardasP. [Malondialdehyde (MDA) as a lipid peroxidation marker]. Wiad Lek (2004) 57:453–5.

  • Google Scholar

• 266

  JammesYRetornazF. Understanding neuromuscular disorders in chronic fatigue syndrome. F1000Res. (2019) 8. doi: 10.12688/f1000research

  • CrossRef
  • Google Scholar

• 267

  FenouilletEVigourouxASteinbergJGChagvardieffARetornazFGuieuRet al. Association of biomarkers with health-related quality of life and history of stressors in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med (2016) 14:251.

  • Google Scholar

• 268

  CatalánVFrühbeckGGómez-AmbrosiJ. Chapter 8 - inflammatory and oxidative stress markers in skeletal muscle of obese subjects. In: del MoralAMAguilera GarcíaCM, editors. Obesity. Academic Press (2018).

  • Google Scholar

• 269

  GermainARuppertDLevineSMHansonMR. Prospective biomarkers from plasma metabolomics of myalgic encephalomyelitis/chronic fatigue syndrome implicate redox imbalance in disease symptomatology. Metabolites. (2018) 8. doi: 10.3390/metabo8040090

  • CrossRef
  • Google Scholar

• 270

  ChiabrandoDVinchiFFioritoVMercurioSTolosanoE. Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Front Pharmacol (2014) 5:61.

  • Google Scholar

• 271

  OgunASAdeyinkaA. Biochemistry, transferrin. In: StatPearls. Treasure Island (FL: StatPearls Publishing (2023).

  • Google Scholar

• 272

  ReglandBAnderssonMAbrahamssonLBagbyJDyrehagLEGottfriesCG. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol (1997) 26:301–7.

  • Google Scholar

• 273

  WeissN. Mechanisms of increased vascular oxidant stress in hyperhomocys-teinemia and its impact on endothelial function. Curr Drug Metab (2005) 6:27–36.

  • Google Scholar

• 274

  MorrisGBerkMKleinHWalderKGaleckiPMaesM. Nitrosative stress, hypernitrosylation, and autoimmune responses to nitrosylated proteins: New pathways in neuroprogressive disorders including depression and chronic fatigue syndrome. Mol Neurobiol (2017) 54:4271–91.

  • Google Scholar

• 275

  PallML. Levels of nitric oxide synthase product citrulline are elevated in sera of chronic fatigue syndrome patients. J Chronic Fatigue Syndrome (2002) 10:37–41.

  • Google Scholar

• 276

  LubosEHandyDELoscalzoJ. Role of oxidative stress and nitric oxide in atherothrombosis. Front Biosci (2008) 13:5323–44.

  • Google Scholar

• 277

  PoznyakAVNikiforovNGMarkinAMKashirskikhDAMyasoedovaVAGerasimovaEVet al. Overview of OxLDL and its impact on cardiovascular health: Focus on atherosclerosis. Front Pharmacol (2021) 11.

  • Google Scholar

• 278

  BrenuEWHuthTKHardcastleSLFullerKKaurMJohnstonSet al. Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis. Int Immunol (2014) 26:233–42.

  • Google Scholar

• 279

  LaforgeMElbimCFrèreCHémadiMMassaadCNussPet al. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nat Rev Immunol (2020) 20:515–6.

  • Google Scholar

• 280

  MiddletonEAHeXYDenormeFCampbellRANgDSalvatoreSPet al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood (2020) 136:1169–79.

  • Google Scholar

• 281

  ZuoYYalavarthiSShiHGockmanKZuoMMadisonJAet al. Neutrophil extracellular traps in COVID-19. JCI Insight (2020) 5.

  • Google Scholar

• 282

  VeenithTMartinHLe BreuillyMWhitehouseTGao-SmithFDuggalNet al. High generation of reactive oxygen species from neutrophils in patients with severe COVID-19. Sci Rep (2022) 12:10484.

  • Google Scholar

• 283

  ShunguDCWeiduschatNMurroughJWMaoXPillemerSDykeJPet al. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR BioMed. (2012) 25:1073–87. doi: 10.1002/nbm.2772

  • CrossRef
  • Google Scholar

• 284

  SongJKangSMLeeWTParkKALeeKMLeeJE. Glutathione protects brain endothelial cells from hydrogen peroxide-induced oxidative stress by increasing nrf2 expression. Exp Neurobiol (2014) 23:93–103.

  • Google Scholar

• 285

  KwonDHChaHJLeeHHongSHParkCParkSHet al. Protective effect of glutathione against oxidative stress-induced cytotoxicity in RAW 264.7 macrophages through activating the nuclear factor erythroid 2-related factor-2/Heme oxygenase-1 pathway. . Antioxidants (Basel) (2019) 8.

  • Google Scholar

• 286

  KennedyGKhanFHillAUnderwoodCBelchJJ. Biochemical and vascular aspects of pediatric chronic fatigue syndrome. Arch Pediatr Adolesc Med (2010) 164:817–23.

  • Google Scholar

• 287

  KawashimaASekizawaAKoideKHasegawaJSatohKArakakiTet al. Vitamin c induces the reduction of oxidative stress and paradoxically stimulates the apoptotic gene expression in extravillous trophoblasts derived from first-trimester tissue. Reprod Sci (2015) 22:783–90.

  • Google Scholar

• 288

  MiwaKFujitaM. Fluctuation of serum vitamin e (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome. Heart Vessels (2010) 25:319–23.

  • Google Scholar

• 289

  SuraiPF. Natural antioxidants in avian nutrition and reproduction. Nottingham University Press Nottingham (2002).

  • Google Scholar

• 290

  MiwaKFujitaM. Increased oxidative stress suggested by low serum vitamin e concentrations in patients with chronic fatigue syndrome. Int J Cardiol (2009) 136:238–9.

  • Google Scholar

• 291

  TuckerJMTownsendDM. Alpha-tocopherol: roles in prevention and therapy of human disease. BioMed Pharmacother (2005) 59:380–7.

  • Google Scholar

• 292

  AokiTMiyakoshiHUsudaYHerbermanRB. Low NK syndrome and its relationship to chronic fatigue syndrome. Clin Immunol Immunopathol (1993) 69:253–65.

  • Google Scholar

• 293

  FraAYoboueEDSitiaR. Cysteines as redox molecular switches and targets of disease. Front Mol Neurosci (2017) 10:167.

  • Google Scholar

• 294

  SweetmanERyanMEdgarCMacKayAVallingsRTateW. Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Int J Immunopathol Pharmacol. (2019) 33:2058738418820402. doi: 10.1177/2058738418820402

  • CrossRef
  • Google Scholar

• 295

  FengDXuDMurakoshiNTajiriKQinRYonebayashiSet al. Nicotinamide phosphoribosyltransferase (Nampt)/Nicotinamide adenine dinucleotide (NAD) axis suppresses atrial fibrillation by modulating the calcium handling pathway. Int J Mol Sci (2020) 21.

  • Google Scholar

• 296

  TedeschiPMBansalNKerriganJEAbaliEEScottoKWBertinoJR. NAD+ kinase as a therapeutic target in cancer. Clin Cancer Res (2016) 22:5189–95.

  • Google Scholar

• 297

  SuárezAGuillamóERoigTBlázquezAAlegreJBermúdezJet al. Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study. J Womens Health (Larchmt). (2010) 19:1073–7. doi: 10.1089/jwh.2008.1255

  • CrossRef
  • Google Scholar

• 298

  Pérez-TorresIManzano-PechLRubio-RuízMESotoMEGuarner-LansV. Nitrosative stress and its association with cardiometabolic disorders. Molecules. (2020) 25:2555. doi: 10.3390/molecules25112555

  • CrossRef
  • Google Scholar

• 299

  JammesYSteinbergJGOlivierMBrerro-SabyCCondoJRavailheSet al. The mechanisms of the widespread production of phosphorylated HSP25 after fatiguing muscle stimulation. J Exp Biol. (2013) 216:3620–6. doi: 10.1242/jeb.088898

  • CrossRef
  • Google Scholar

• 300

  WhithamMFortesMB. Heat shock protein 72: release and biological significance during exercise. Front Biosci. (2008) 13:1328–39. doi: 10.2741/2765

  • CrossRef
  • Google Scholar

• 301

  NobleE. Heat shock proteins and their induction with exercise. Exercise and stress response: the role of stress proteins. Barcelona: Boca Raton. (2002), 43–78. doi: 10.1201/CRCEXEPHYSIO

  • CrossRef
  • Google Scholar

• 302

  JammesYSteinbergJGDelliauxSBrégeonF. Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. J Intern Med. (2009) 266:196–206. doi: 10.1111/j.1365-2796.2009.02079.x

  • CrossRef
  • Google Scholar

• 303

  JammesYSteinbergJGDelliauxS. Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins. J Intern Med. (2012) 272:74–84. doi: 10.1111/j.1365-2796.2011.02488.x

  • CrossRef
  • Google Scholar

• 304

  GerwynMMaesM. Mechanisms explaining muscle fatigue and muscle pain in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a review of recent findings. Curr Rheumatol Rep. (2017) 19:1. doi: 10.1007/s11926-017-0628-x

  • CrossRef
  • Google Scholar

• 305

  BlauensteinerJBertinatRLeónLERiedererMSepúlvedaNWestermeierF. Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients. Sci Rep. (2021) 11:10604. doi: 10.1038/s41598-021-89834-9

  • CrossRef
  • Google Scholar

• 306

  ScherbakovNSzklarskiMHartwigJSotznyFLorenzSMeyerAet al. Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. ESC Heart Fail. (2020) 7:1064–71. doi: 10.1002/ehf2.12633

  • CrossRef
  • Google Scholar

• 307

  NewtonDJKennedyGChanKKLangCCBelchJJKhanF. Large and small artery endothelial dysfunction in chronic fatigue syndrome. Int J Cardiol. (2012) 154:335–6. doi: 10.1016/j.ijcard.2011.10.030

  • CrossRef
  • Google Scholar

• 308

  PoberJSSessaWC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. (2007) 7:803–15. doi: 10.1038/nri2171

  • CrossRef
  • Google Scholar

• 309

  BaiBYangYWangQLiMTianCLiuYet al. NLRP3 inflammasome in endothelial dysfunction. Cell Death Dis. (2020) 11:776. doi: 10.1038/s41419-020-02985-x

  • CrossRef
  • Google Scholar

• 310

  NewtonJOkonkwoOSutcliffeKSethAShinJJonesD. Symptoms of autonomic dysfunction in chronic fatigue syndrome. QJM: Int J Med. (2007) 100:519–26. doi: 10.1093/qjmed/hcm057

  • CrossRef
  • Google Scholar

• 311

  SørlandKSandvikMKRekelandIGRibuLSmåstuenMCMellaOet al. Reduced endothelial function in myalgic encephalomyelitis/chronic fatigue syndrome-results from open-label cyclophosphamide intervention study. Front Med (Lausanne). (2021) 8:642710. doi: 10.3389/fmed.2021.642710

  • CrossRef
  • Google Scholar

• 312

  YangC-ABauerSHoY-CSotznyFChangJ-GScheibenbogenC. The expression signature of very long non-coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome. J Trans Med. (2018) 16:231. doi: 10.1186/s12967-018-1600-x

  • CrossRef
  • Google Scholar

• 313

  NunesJMKrugerAProalAKellDBPretoriusE. The occurrence of hyperactivated platelets and fibrinaloid microclots in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Pharm (Basel) 15. (2022). doi: 10.21203/rs.3.rs-1727226/v2

  • CrossRef
  • Google Scholar

• 314

  MartinLKoczeraPZechendorfESchuerholzT. The endothelial glycocalyx: new diagnostic and therapeutic approaches in sepsis. BioMed Res Int. (2016) 2016:3758278. doi: 10.1155/2016/3758278

  • CrossRef
  • Google Scholar

• 315

  SantulliG. MicroRNAs and endothelial (Dys) function. J Cell Physiol. (2016) 231:1638–44. doi: 10.1002/jcp.v231.8

  • CrossRef
  • Google Scholar

• 316

  KauppinenASuuronenTOjalaJKaarnirantaKSalminenA. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal. (2013) 25:1939–48. doi: 10.1016/j.cellsig.2013.06.007

  • CrossRef
  • Google Scholar

• 317

  MattagajasinghIKimCSNaqviAYamamoriTHoffmanTAJungSBet al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U.S.A. (2007) 104:14855–60. doi: 10.1073/pnas.0704329104

  • CrossRef
  • Google Scholar

• 318

  FarahCMichelLYMBalligandJL. Nitric oxide signalling in cardiovascular health and disease. Nat Rev Cardiol. (2018) 15:292–316. doi: 10.1038/nrcardio.2017.224

  • CrossRef
  • Google Scholar

• 319

  FanWFangRWuXLiuJFengMDaiGet al. Shear-sensitive microRNA-34a modulates flow-dependent regulation of endothelial inflammation. J Cell Sci (2015) 128:70–80.

  • Google Scholar

• 320

  GouLZhaoLSongWWangLLiuJZhangHet al. Inhibition of miR-92a suppresses oxidative stress and improves endothelial function by upregulating heme oxygenase-1 in db/db mice. Antioxid Redox Signal (2018) 28:358–70.

  • Google Scholar

• 321

  GuoYLiPGaoLZhangJYangZBledsoeGet al. Kallistatin reduces vascular senescence and aging by regulating microRNA-34a-SIRT1 pathway. Aging Cell (2017) 16:837–46.

  • Google Scholar

• 322

  MurugaiyanGda CunhaAPAjayAKJollerNGaroLPKumaradevanSet al. MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest (2015) 125:1069–80.

  • Google Scholar

• 323

  RouasRFayyad-KazanHEl ZeinNLewallePRothéFSimionAet al. Human natural treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol (2009) 39:1608–18.

  • Google Scholar

• 324

  XuFZhouF. Inhibition of microRNA-92a ameliorates lipopolysaccharide-induced endothelial barrier dysfunction by targeting ITGA5 through the PI3K/Akt signaling pathway in human pulmonary microvascular endothelial cells. Int Immunopharmacol (2020) 78:106060.

  • Google Scholar

• 325

  YangHHChenYGaoCYCuiZTYaoJM. Protective effects of MicroRNA-126 on human cardiac microvascular endothelial cells against Hypoxia/Reoxygenation-induced injury and inflammatory response by activating PI3K/Akt/eNOS signaling pathway. Cell Physiol Biochem (2017) 42:506–18.

  • Google Scholar

• 326

  ZhangHLiuJQuDWangLLuoJYLauCWet al. Inhibition of miR-200c restores endothelial function in diabetic mice through suppression of COX-2. Diabetes (2016) 65:1196–207.

  • Google Scholar

• 327

  GuoYLiPBledsoeGYangZRChaoLChaoJ. Kallistatin inhibits TGF-β-induced endothelial-mesenchymal transition by differential regulation of microRNA-21 and eNOS expression. Exp Cell Res (2015) 337:103–10.

  • Google Scholar

• 328

  HartMWalch-RückheimBFriedmannKSRheinheimerSTänzerTGlombitzaBet al. miR-34a: a new player in the regulation of t cell function by modulation of NF-κB signaling. Cell Death Dis (2019) 10:46.

  • Google Scholar

• 329

  NelsonMJBahlJSBuckleyJDThomsonRLDavisonK. Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis. Med (Baltimore). (2019) 98:e17600. doi: 10.1097/MD.0000000000017600

  • CrossRef
  • Google Scholar

• 330

  MeeusMGoubertDDe BackerFStruyfFHermansLCoppietersIet al. Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: A systematic review. Semin Arthritis Rheumatism. (2013) 43:279–87. doi: 10.1016/j.semarthrit.2013.03.004

  • CrossRef
  • Google Scholar

• 331

  SłomkoJEstévez-LópezFKujawskiSZawadka-KunikowskaMTafil-KlaweMKlaweJJet al. Autonomic phenotypes in chronic fatigue syndrome (CFS) are associated with illness severity: A cluster analysis. J Clin Med. (2020) 9. doi: 10.3390/jcm9082531

  • CrossRef
  • Google Scholar

• 332

  Martı́nez-Martı́nezL-AMoraTVargasAFuentes-IniestraMMartı́nez-Lavı́nM. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. JCR: J Clin Rheumatol (2014) 20:146–50. doi: 10.1097/RHU.0000000000000089

  • CrossRef
  • Google Scholar

• 333

  OrjatsaloMAlakuijalaAPartinenM. Autonomic nervous system functioning related to nocturnal sleep in patients with chronic fatigue syndrome compared to tired controls. J Clin Sleep Med (2018) 14:163–71. doi: 10.5664/jcsm.6924

  • CrossRef
  • Google Scholar

• 334

  SistoSATappWDrastalSBergenMDeMasiICorderoDet al. Vagal tone is reduced during paced breathing in patients with the chronic fatigue syndrome. Clin Autonomic Res. (1995) 5:139–43. doi: 10.1007/BF01826195

  • CrossRef
  • Google Scholar

• 335

  JonesDEJHollingsworthKGTaylorRBlamireAMNewtonJL. Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome. J Internal Med. (2010) 267:394–401. doi: 10.1111/j.1365-2796.2009.02160.x

  • CrossRef
  • Google Scholar

• 336

  StewartJM. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterised by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res. (2000) 48:218–26. doi: 10.1203/00006450-200008000-00016

  • CrossRef
  • Google Scholar

• 337

  BeaumontABurtonARLemonJBennettBKLloydAVollmer-ConnaU. Reduced cardiac vagal modulation impacts on cognitive performance in chronic fatigue syndrome. PloS One. (2012) 7:e49518. doi: 10.1371/journal.pone.0049518

  • CrossRef
  • Google Scholar

• 338

  WyllerVBSaulJPWalløeLThaulowE. Sympathetic cardiovascular control during orthostatic stress and isometric exercise in adolescent chronic fatigue syndrome. Eur J Appl Physiol. (2008) 102:623–32. doi: 10.1007/s00421-007-0634-1

  • CrossRef
  • Google Scholar

• 339

  De BeckerPDendalePDe MeirleirKCampineIVandenborneKHagersY. Autonomic testing in patients with chronic fatigue syndrome. Am J Med. (1998) 105:22S–6S. doi: 10.1016/S0002-9343(98)00168-5

  • CrossRef
  • Google Scholar

• 340

  RimesKALievesleyKChalderT. Stress vulnerability in adolescents with chronic fatigue syndrome: experimental study investigating heart rate variability and skin conductance responses. J Child Psychol Psychiatry. (2017) 58:851–8. doi: 10.1111/jcpp.12711

  • CrossRef
  • Google Scholar

• 341

  Van CauwenberghDNijsJKosDVan WeijnenLStruyfFMeeusM. Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review. Eur J Clin Invest. (2014) 44:516–26. doi: 10.1111/eci.12256

  • CrossRef
  • Google Scholar

• 342

  FrithJZalewskiPKlaweJJPairmanJBitnerATafil-KlaweMet al. Impaired blood pressure variability in chronic fatigue syndrome—a potential biomarker. QJM: Int J Med. (2012) 105:831–8. doi: 10.1093/qjmed/hcs085

  • CrossRef
  • Google Scholar

• 343

  BurtonARRahmanKKadotaYLloydAVollmer-ConnaU. Reduced heart rate variability predicts poor sleep quality in a case–control study of chronic fatigue syndrome. Exp Brain Res. (2010) 204:71–8. doi: 10.1007/s00221-010-2296-1

  • CrossRef
  • Google Scholar

• 344

  YatacoATaloHRowePKassDABergerRDCalkinsH. Comparison of heart rate variability in patients with chronic fatigue syndrome and controls. Clin Autonomic Res. (1997) 7:293–7. doi: 10.1007/BF02267720

  • CrossRef
  • Google Scholar

• 345

  KaurJKrishnanACSenadorDAlvarezAHannaHWO’LearyDS. Altered arterial baroreflex-muscle metaboreflex interaction in heart failure. Am J Physiol Heart Circ Physiol (2018). doi: 10.1152/ajpheart.00338.2018

  • CrossRef
  • Google Scholar

• 346

  YlikorkalaODawoodMY. New concepts in dysmenorrhea. Am J Obstetrics Gynecology. (1978) 130:833–47. doi: 10.1016/0002-9378(78)90019-4

  • CrossRef
  • Google Scholar

• 347

  MullinsRJMaliasMAHudgensRW. Isoproterenol inhibits the increase in microvascular membrane permeability produced by bradykinin. J Trauma. (1989) 29:1053–63. doi: 10.1097/00005373-198908000-00002

  • CrossRef
  • Google Scholar

• 348

  SzabóGMagyarZ. Effect of histamine and bradykinin on lymph and tissue fluid composition in the rabbit hindlimb: evidence for two compartments in tissue fluid. Acta Physiol Acad Sci Hung. (1982) 59:15–27.

  • Google Scholar

• 349

  BergDBergLHCouvarasJHarrisonH. Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid antibody syndrome: an explanatory model and approach to laboratory diagnosis. Blood Coagul Fibrinolysis. (1999) 10:435–8. doi: 10.1097/00001721-199910000-00006

  • CrossRef
  • Google Scholar

• 350

  HannanKLBergDEBaumzweigerWHarrisonHHBergLHRamirezRet al. Activation of the coagulation system in Gulf War Illness: a potential pathophysiologic link with chronic fatigue syndrome. A Lab approach to diagnosis. Blood Coagul Fibrinolysis (2000) 11:673–8. doi: 10.1097/00001721-200010000-00013

  • CrossRef
  • Google Scholar

• 351

  BrewerJHBergD. Hypercoaguable state associated with active human herpesvirus-6 (HHV-6) viremia in patients with chronic fatigue syndrome. J Chronic Fatigue Syndrome. (2001) 8:111–6. doi: 10.1300/J092v08n03_10

  • CrossRef
  • Google Scholar

• 352

  KennedyGNorrisGSpenceVMcLarenMBelchJJ. Is chronic fatigue syndrome associated with platelet activation? Blood Coagul Fibrinolysis (2006) 17:89–92. doi: 10.1097/01.mbc.0000214705.80997.73

  • CrossRef
  • Google Scholar

• 353

  PretoriusEMbotweSBesterJRobinsonCJKellDB. Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highlysubstoichiometric levels of bacterial lipopolysaccharide. J R Soc Interface (2016) 13. doi: 10.1101/053538

  • CrossRef
  • Google Scholar

• 354

  NatelsonBHWeaverSATsengCLOttenwellerJE. Spinal fluid abnormalities in patients with chronic fatigue syndrome. Clin Diagn Lab Immunol (2005) 12:52–5. doi: 10.1128/CDLI.12.1.52-55.2005

  • CrossRef
  • Google Scholar

• 355

  SferaAOsorioCZapata Martı́n Del CampoCMPereidaSMaurerSMaldonadoJCet al. Endothelial senescence and chronic fatigue syndrome, a COVID-19 based hypothesis. Front Cell Neurosci (2021) 15:673217. doi: 10.3389/fncel.2021.673217

  • CrossRef
  • Google Scholar

• 356

  CostaDCTannockCBrostoffJ. Brainstem perfusion is impaired in chronic fatigue syndrome. Qjm. (1995) 88:767–73.

  • Google Scholar

• 357

  TirelliUChierichettiFTavioMSimonelliCBianchinGZancoPet al. Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data. Am J Med (1998) 105. doi: 10.1016/S0002-9343(98)00179-X

  • CrossRef
  • Google Scholar

• 358

  KuratsuneHYamagutiKLindhGEvengårdBHagbergGMatsumuraKet al. Brain regions involved in fatigue sensation: reduced acetylcarnitine uptake into the brain. Neuroimage. (2002) 17:1256–65. doi: 10.1006/nimg.2002.1260

  • CrossRef
  • Google Scholar

• 359

  WirthKJScheibenbogenC. Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). J Transl Med (2021) 19:162. doi: 10.1186/s12967-021-02833-2

  • CrossRef
  • Google Scholar

• 360

  van CampenCVerheugtFWARowePCVisserFC. Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography. Clin Neurophysiol Pract (2020) 5:50–8. doi: 10.1016/j.cnp.2020.01.003

  • CrossRef
  • Google Scholar

• 361

  BragéeBMichosADrumBFahlgrenMSzulkinRBertilsonBC. Signs of intracranial hypertension, hypermobility, and craniocervical obstructions in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol (2020) 11:828. doi: 10.3389/fneur.2020.00828

  • CrossRef
  • Google Scholar

• 362

  HulensMRasschaertRVansantGStalmansIBruyninckxFDankaertsW. The link between idiopathic intracranial hypertension, fibromyalgia, and chronic fatigue syndrome: exploration of a shared pathophysiology. J Pain Res (2018) 11:3129–40. doi: 10.2147/JPR

  • CrossRef
  • Google Scholar

• 363

  TohidpourAMorgunAVBoitsovaEBMalinovskayaNAMartynovaGPKhilazhevaEDet al. Neuroinflammation and infection: molecular mechanisms associated with dysfunction of neurovascular unit. Front Cell Infect Microbiol (2017) 7:276. doi: 10.1146/annurev.nutr.26.061505.111258

  • CrossRef
  • Google Scholar

• 364

  HotamisligilGS. Inflammation, metaflammation and immunometabolic disorders. Nature. (2017) 542:177–85. doi: 10.1038/nature21363

  • CrossRef
  • Google Scholar

• 365

  CahillGFJr.. Fuel metabolism in starvation. Annu Rev Nutr (2006) 26:1–22.

  • Google Scholar

• 366

  van HallG. The physiological regulation of skeletal muscle fatty acid supply and oxidation during moderate-intensity exercise. Sports Med (2015) 45 Suppl 1:S23–32. doi: 10.1007/s40279-015-0394-8

  • CrossRef
  • Google Scholar

• 367

  WagenmakersAJ. Muscle amino acid metabolism at rest and during exercise: role in human physiology and metabolism. Exerc Sport Sci Rev (1998) 26:287–314. doi: 10.1249/00003677-199800260-00013

  • CrossRef
  • Google Scholar

• 368

  MyhillSBoothNEMcLaren-HowardJ. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med (2009) 2:1–16.

  • Google Scholar

• 369

  HoldenSMaksoudREaton-FitchNCabanasHStainesDMarshall-GradisnikS. A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease. J Transl Med (2020) 18:290. doi: 10.1186/s12967-020-02452-3

  • CrossRef
  • Google Scholar

• 370

  BoothNEMyhillSMcLaren-HowardJ. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med (2012) 5:208–20.

  • Google Scholar

• 371

  Castro-MarreroJCorderoMDSáez-FrancasNJimenez-GutierrezCAguilar- MontillaFJAlisteLet al. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? Antioxid Redox Signal (2013) 19:1855–60. doi: 10.1089/ars.2013.5346

  • CrossRef
  • Google Scholar

• 372

  MyhillSBoothNEMcLaren-HowardJ. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)-a clinical audit. Int J Clin Exp Med (2013) 6:1.

  • Google Scholar

• 373

  MorrisGMaesM. Mitochondrial dysfunctions in myalgic encephalomyelitis/ chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis (2014) 29:19–36. doi: 10.1007/s11011-013-9435-x

  • CrossRef
  • Google Scholar

• 374

  MissailidisDAnnesleySJFisherPR. Pathological mechanisms underlying myalgic encephalomyelitis/chronic fatigue syndrome. Diagnostics (Basel). (2019) 9. doi: 10.20944/preprints201907.0196.v1

  • CrossRef
  • Google Scholar

• 375

  MaesMTwiskFNMRingelK. Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. Psychother Psychosomatics. (2012) 81:286–95. doi: 10.1159/000336803

  • CrossRef
  • Google Scholar

• 376

  SadatomiDNakashioyaKMamiyaSHondaSKameyamaYYamamuraYet al. Mitochondrial function is required for extracellular ATP-induced NLRP3= inflammasome activation. J Biochem (2017) 161:503–12. doi: 10.1093/jb/mvw098

  • CrossRef
  • Google Scholar

• 377

  MillsELKellyBO’NeillLAJ. Mitochondria are the powerhouses of immunity. Nat Immunol (2017) 18:488–98. doi: 10.1038/ni.3704

  • CrossRef
  • Google Scholar

• 378

  BredaCNSDavanzoGGBassoPJSaraiva CâmaraNOMoraes-VieiraPMM. Mitochondria as central hub of the immune system. Redox Biol (2019) 26:101255. doi: 10.1016/j.redox.2019.101255

  • CrossRef
  • Google Scholar

• 379

  WeinbergSESenaLAChandelNS. Mitochondria in the regulation of innate and adaptive immunity. Immunity. (2015) 42:406–17. doi: 10.1016/j.immuni.2015.02.002

  • CrossRef
  • Google Scholar

• 380

  MurphyMP. How mitochondria produce reactive oxygen species. Biochem J (2009) 417:1–13. doi: 10.1042/BJ20081386

  • CrossRef
  • Google Scholar

• 381

  AbateGVezzoliMSandriMRungratanawanichWMemoMUbertiD. Mitochondria and cellular redox state on the route from ageing to Alzheimer’s disease. Mech Ageing Dev (2020) 192:111385. doi: 10.1016/j.mad.2020.111385

  • CrossRef
  • Google Scholar

• 382

  BehanWMMoreIABehanPO. Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol. (1991) 83:61–5. doi: 10.1007/BF00294431

  • CrossRef
  • Google Scholar

• 383

  PlioplysAVPlioplysS. Electron-microscopic investigation of muscle mitochondria in chronic fatigue syndrome. Neuropsychobiology. (1995) 32:175–81. doi: 10.1159/000119233

  • CrossRef
  • Google Scholar

• 384

  LawsonNHsiehCHMarchDWangX. Elevated energy production in chronic fatigue syndrome patients. J Nat Sci. (2016) 2.

  • Google Scholar

• 385

  TomasCBrownAStrassheimVElsonJLNewtonJManningP. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PloS One. (2017) 12:e0186802. doi: 10.1371/journal.pone.0186802

  • CrossRef
  • Google Scholar

• 386

  MissailidisDAnnesleySJAllanCYSanislavOLidburyBALewisDPet al. An isolated complex V inefficiency and dysregulated mitochondrial function in immortalised lymphocytes from ME/CFS patients. Int J Mol Sci 21. (2020). doi: 10.20944/preprints201909.0043.v2

  • CrossRef
  • Google Scholar

• 387

  SweetmanEKleffmannTEdgarCde LangeMVallingsRTateW. A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction. J Transl Med. (2020) 18:365. doi: 10.1186/s12967-020-02533-3

  • CrossRef
  • Google Scholar

• 388

  TomasCElsonJLStrassheimVNewtonJLWalkerM. The effect of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) severity on cellular bioenergetic function. PloS One. (2020) 15:e0231136. doi: 10.1371/journal.pone.0231136

  • CrossRef
  • Google Scholar

• 389

  NguyenTStainesDJohnstonSMarshall-GradisnikS. Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: A preliminary investigation. Asian Pac J Allergy Immunol. (2019) 37:102–8. doi: 10.12932/AP-011117-0188. PMID: 29981562

  • CrossRef
  • Google Scholar

• 390

  RutherfordGManningPNewtonJL. Understanding muscle dysfunction in chronic fatigue syndrome. J Aging Res. (2016) 2016:2497348. doi: 10.1155/2016/2497348

  • CrossRef
  • Google Scholar

• 391

  MaesMTwiskFN. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. (2009) 30:677–93.

  • Google Scholar

• 392

  BarteeLAndersonC. Mt Hood Community College Biology 101: An overview of cellular respiration, Open Oregon Educational Resources. (2016).

  • Google Scholar

• 393

  van CampenCLMRowePCVisserFC. Two-day cardiopulmonary exercise testing in females with a severe grade of myalgic encephalomyelitis/chronic fatigue syndrome: comparison with patients with mild and moderate disease. Healthcare (Basel) 8. (2020). doi: 10.3390/healthcare8030192

  • CrossRef
  • Google Scholar

• 394

  StevensSSnellCStevensJKellerBVanNessJM. Cardiopulmonary exercise test methodology for assessing exertion intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Front Pediatr. (2018) 6:242. doi: 10.3389/fped.2018.00242

  • CrossRef
  • Google Scholar

• 395

  MurroughJWMaoXCollinsKAKellyCAndradeGNestadtPet al. Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. NMR BioMed. (2010) 23:643–50. doi: 10.1002/nbm.1512

  • CrossRef
  • Google Scholar

• 396

  MathewSJMaoXKeeganKALevineSMSmithELHeierLAet al. Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalised anxiety disorder: an in vivo 3. 0 T (1)H MRS Imaging study. NMR BioMed. (2009) 22:251–8. doi: 10.1002/nbm.1315

  • CrossRef
  • Google Scholar

• 397

  LienKJohansenBVeierødMBHaslestadASBøhnSKMelsomMNet al. Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. (2019) 7:e14138. doi: 10.14814/phy2.14138

  • CrossRef
  • Google Scholar

• 398

  SnellCRStevensSRDavenportTEVan NessJM. Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome. Phys Ther. (2013) 93:1484–92. doi: 10.2522/ptj.20110368

  • CrossRef
  • Google Scholar

• 399

  VermeulenRCVermeulen van EckIW. Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome. J Transl Med. (2014) 12:20. doi: 10.1186/1479-5876-12-20

  • CrossRef
  • Google Scholar

• 400

  FeganKGBehanPOBellEJ. Myalgic encephalomyelitis–report of an epidemic. J R Coll Gen Pract. (1983) 33:335–7.

  • Google Scholar

• 401

  TomasCNewtonJ. Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review. Biochem Soc Trans. (2018) 46:547–53. doi: 10.1042/BST20170503

  • CrossRef
  • Google Scholar

• 402

  JonesDEHollingsworthKGJakovljevicDGFattakhovaGPairmanJBlamireAMet al. Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study. Eur J Clin Invest. (2012) 42:186–94. doi: 10.1111/j.1365-2362.2011.02567.x

  • CrossRef
  • Google Scholar

• 403

  ChaudhuriABehanPO. In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids. (2004) 71:181–3. doi: 10.1016/j.plefa.2004.03.009

  • CrossRef
  • Google Scholar

• 404

  LengertNDrosselB. In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Biophys Chem. (2015) 202:21–31. doi: 10.1016/j.bpc.2015.03.009

  • CrossRef
  • Google Scholar

• 405

  GermainABarupalDKLevineSMHansonMR. Comprehensive circulatory metabolomics in ME/CFS reveals disrupted metabolism of acyl lipids and steroids. Metabolites. (2020) 10. doi: 10.3390/metabo10010034

  • CrossRef
  • Google Scholar

• 406

  Nagy-SzakalDBarupalDKLeeBCheXWilliamsBLKahnEJRet al. Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. Sci Rep. (2018) 8:10056. doi: 10.1038/s41598-018-28477-9

  • CrossRef
  • Google Scholar

• 407

  NaviauxRKNaviauxJCLiKBrightATAlaynickWAWangLet al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U.S.A. (2016) 113:E5472–80. doi: 10.1073/pnas.1607571113

  • CrossRef
  • Google Scholar

• 408

  YamanoESugimotoMHirayamaAKumeSYamatoMJinGet al. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Sci Rep. (2016) 6:34990. doi: 10.1038/srep34990

  • CrossRef
  • Google Scholar

• 409

  NiblettSHKingKEDunstanRHClifton-BlighPHoskinLARobertsTKet al. Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome. Exp Biol Med (Maywood). (2007) 232:1041–9. doi: 10.3181/0702-RM-44

  • CrossRef
  • Google Scholar

• 410

  MaloneyEMBonevaRSLinJMReevesWC. Chronic fatigue syndrome is associated with metabolic syndrome: results from a case-control study in Georgia. Metabolism. (2010) 59:1351–7. doi: 10.1016/j.metabol.2009.12.019

  • CrossRef
  • Google Scholar

• 411

  KitamiTFukudaSKatoTYamagutiKNakatomiYYamanoEet al. Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population. Sci Rep. (2020) 10:19933. doi: 10.1038/s41598-020-77105-y

  • CrossRef
  • Google Scholar

• 412

  ReuterSEEvansAM. Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitine palmitoyltransferase-I activity. J Internal Med. (2011) 270:76–84. doi: 10.1111/j.1365-2796.2010.02341.x

  • CrossRef
  • Google Scholar

• 413

  HuthTKEaton-FitchNStainesDMarshall-GradisnikS. A systematic review of metabolomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID). J Transl Med. (2020) 18:198. doi: 10.1186/s12967-020-02356-2

  • CrossRef
  • Google Scholar

• 414

  NaviauxRK. Incomplete healing as a cause of aging: the role of mitochondria and the cell danger response. Biol (Basel). (2019) 8. doi: 10.3390/biology8020027

  • CrossRef
  • Google Scholar

• 415

  NaviauxRK. Perspective: Cell danger response Biology-The new science that connects environmental health with mitochondria and the rising tide of chronic illness. Mitochondrion. (2020) 51:40–5. doi: 10.1016/j.mito.2019.12.005

  • CrossRef
  • Google Scholar

• 416

  NaviauxRK. Metabolic features of the cell danger response. Mitochondrion. (2014) 16:7–17. doi: 10.1016/j.mito.2013.08.006

  • CrossRef
  • Google Scholar

• 417

  Costa-MattioliMWalterP. The integrated stress response: From mechanism to disease. Science. (2020) 368. doi: 10.1126/science.aat5314

  • CrossRef
  • Google Scholar

• 418

  PoonDCHoYSChiuKWongHLChangRC. Sickness: From the focus on cytokines, prostaglandins, and complement factors to the perspectives of neurons. Neurosci Biobehav Rev. (2015) 57:30–45. doi: 10.1016/j.neubiorev.2015.07.015

  • CrossRef
  • Google Scholar

• 419

  MissailidisDSanislavOAllanCYAnnesleySJFisherPR. Cell-based blood biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome. Int J Mol Sci. (2020) 21. doi: 10.20944/preprints202002.0029.v1

  • CrossRef
  • Google Scholar

• 420

  PivovarovaNBAndrewsSB. Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J. (2010) 277:3622–36. doi: 10.1111/j.1742-4658.2010.07754.x

  • CrossRef
  • Google Scholar

• 421

  AngajalaALimSPhillipsJBKimJHYatesCYouZet al. Diverse roles of mitochondria in immune responses: novel insights into immuno-metabolism. Front Immunol. (2018) 9:1605. doi: 10.3389/fimmu.2018.01605

  • CrossRef
  • Google Scholar

• 422

  JohnstonSCStainesDRMarshall-GradisnikSM. Epidemiological characteristics of chronic fatigue syndrome/myalgic encephalomyelitis in Australian patients. Clin Epidemiol. (2016) 8:97–107. doi: 10.2147/CLEP

  • CrossRef
  • Google Scholar

• 423

  LattieEGAntoniMHFletcherMAPenedoFCzajaSLopezCet al. Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome. Brain Behav Immun. (2012) 26:849–58. doi: 10.1016/j.bbi.2012.02.008

  • CrossRef
  • Google Scholar

• 424

  BalinasCEaton-FitchNMaksoudRStainesDMarshall-GradisnikS. Impact of life stressors on myalgic encephalomyelitis/chronic fatigue syndrome symptoms: an Australian longitudinal study. Int J Environ Res Public Health. (2021) 18. doi: 10.3390/ijerph182010614

  • CrossRef
  • Google Scholar

• 425

  TomasCNewtonJWatsonS. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neurosci. (2013) 2013:784520. doi: 10.1155/2013/784520

  • CrossRef
  • Google Scholar

• 426

  TakLMCleareAJOrmelJManoharanAKokICWesselySet al. Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. Biol Psychol. (2011) 87:183–94. doi: 10.1016/j.biopsycho.2011.02.002

  • CrossRef
  • Google Scholar

• 427

  HannibalKEBishopMD. Chronic stress, cortisol dysfunction, and pain: a psychoneuroendocrine rationale for stress management in pain rehabilitation. Phys Ther. (2014) 94:1816–25. doi: 10.2522/ptj.20130597

  • CrossRef
  • Google Scholar

• 428

  Torres-HardingSSorensonMJasonLMaherKFletcherMAReynoldsNet al. The associations between basal salivary cortisol and illness symptomatology in chronic fatigue syndrome. J Appl Biobehav Res. (2008) 13:157–80. doi: 10.1111/j.1751-9861.2008.00033.x

  • CrossRef
  • Google Scholar

• 429

  MorrisGAndersonGMaesM. Hypothalamic-pituitary-adrenal hypofunction in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) as a consequence of activated immune-inflammatory and oxidative and nitrosative pathways. Mol Neurobiol. (2017) 54:6806–19. doi: 10.1007/s12035-016-0170-2

  • CrossRef
  • Google Scholar

• 430

  De BellisABellastellaGPerniceVCirilloPLongoMMaioAet al. Hypothalamic-pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome. J Clin Endocrinol Metab. (2021) 106:e5147–55. doi: 10.1210/clinem/dgab429

  • CrossRef
  • Google Scholar

• 431

  BerwaertsJMoorkensGAbsR. Secretion of growth hormone in patients with chronic fatigue syndrome. Growth Horm IGF Res 8 Suppl B. (1998), 127–9. doi: 10.1016/S1096-6374(98)80036-1

  • CrossRef
  • Google Scholar

• 432

  PanJMaNZhongJYuBWanJZhangW. Age-associated changes in microglia and astrocytes ameliorate blood-brain barrier dysfunction. Mol Ther Nucleic Acids. (2021) 26:970–86. doi: 10.1016/j.omtn.2021.08.030

  • CrossRef
  • Google Scholar

• 433

  AkalinAKormakssonMLiSGarrett-BakelmanFEFigueroaMEMelnickAet al. methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. Genome Biol. (2012) 13:R87. doi: 10.1186/gb-2012-13-10-r87

  • CrossRef
  • Google Scholar

• 434

  DinanTG. Serotonin and the regulation of hypothalamic-pituitary-adrenal axis function. Life Sci. (1996) 58:1683–94. doi: 10.1016/0024-3205(96)00066-5

  • CrossRef
  • Google Scholar

• 435

  PereiraGGilliesHChandaSCorbettMVernonSDMilaniTet al. Acute corticotropin-releasing factor receptor type 2 agonism results in sustained symptom improvement in myalgic encephalomyelitis/chronic fatigue syndrome. Front Syst Neurosci. (2021) 15:698240. doi: 10.3389/fnsys.2021.698240

  • CrossRef
  • Google Scholar

• 436

  JohnsonC. Health rising. (2018). Available at: https://www.healthrising.org [Accessed 17 January 2024].

  • Google Scholar

• 437

  DobryakovaEGenovaHMDeLucaJWylieGR. The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders. Front Neurol. (2015) 6:52. doi: 10.3389/fneur.2015.00052

  • CrossRef
  • Google Scholar

• 438

  JanowskyDSDavisJM. Psychological effects of cholinomimetic agents. In: DavisKLBergerPA, editors. Brain acetylcholine and neuropsychiatric disease. Springer US, Boston, MA (1979). p. 3–14.

  • Google Scholar

• 439

  CasanuevaFFBettiRCellaSGMüllerEEMantegazzaP. Effect of agonists and antagonists of cholinergic neurotransmission on growth hormone release in the dog. Acta Endocrinol (Copenh). (1983) 103:15–20. doi: 10.1530/acta.0.1030015

  • CrossRef
  • Google Scholar

• 440

  BakheitAMBehanPOWatsonWSMortonJJ. Abnormal arginine-vasopressin secretion and water metabolism in patients with postviral fatigue syndrome. Acta Neurol Scand. (1993) 87:234–8. doi: 10.1111/j.1600-0404.1993.tb04108.x

  • CrossRef
  • Google Scholar

• 441

  BakheitAMBehanPODinanTGGrayCEO’KeaneV. Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. Bmj. (1992) 304:1010–2. doi: 10.1136/bmj.304.6833.1010

  • CrossRef
  • Google Scholar

• 442

  CleareAJBearnJAllainTMcGregorAWesselySMurrayRMet al. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J Affect Disord. (1995) 34:283–9. doi: 10.1016/0165-0327(95)00026-J

  • CrossRef
  • Google Scholar

• 443

  MisiakBŁoniewskiIMarliczWFrydeckaDSzulcARudzkiLet al. The HPA axis dysregulation in severe mental illness: Can we shift the blame to gut microbiota? Prog Neuropsychopharmacol Biol Psychiatry. (2020) 102:109951. doi: 10.1016/j.pnpbp.2020.109951

  • CrossRef
  • Google Scholar

• 444

  R.a.P. Moss-MorrisK. Chronic fatigue syndrome. 1st ed. Milton Park, Abingdon-on-Thames, Oxfordshire, England, UK: Routledge (2000).

  • Google Scholar

• 445

  BradleyASFordBBansalAS. Altered functional b cell subset populations in patients with chronic fatigue syndrome compared to healthy controls. Clin Exp Immunol (2013) 172:73–80.

  • Google Scholar

• 446

  KlimasNGSalvatoFRMorganRFletcherMA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol (1990) 28:1403–10.

  • Google Scholar

• 447

  TirelliUMarottaGImprotaSPintoA. Immunological abnormalities in patients with chronic fatigue syndrome. Scandinavian J Immunol (1994) 40:601–8.

  • Google Scholar

• 448

  MilivojevicMCheXBatemanLChengAGarciaBAHornigMet al. Plasma proteomic profiling suggests an association between antigen driven clonal b cell expansion and ME/CFS. PloS One (2020) 15:e0236148.

  • Google Scholar

• 449

  CherukuriAChengPCSohnHWPierceSK. The CD19/CD21 complex functions to prolong b cell antigen receptor signaling from lipid rafts. Immunity (2001) 14:169–79.

  • Google Scholar

• 450

  PersJOJaminCPredine-HugFLydyardPYouinouP. The role of CD5-expressing b cells in health and disease (review). Int J Mol Med (1999) 3:239–45.

  • Google Scholar

• 451

  RivasJLPalenciaTFernándezGGarcíaM. Association of t and NK cell phenotype with the diagnosis of myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). Front Immunol (2018) 9:1028.

  • Google Scholar

• 452

  LandayALJessopCLennetteETLevyJA. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet (1991) 338:707–12.

  • Google Scholar

• 453

  CliffJMKingECLeeJSSepúlvedaNWolfASKingdonCet al. Cellular immune function in myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). Front Immunol (2019) 10:796.

  • Google Scholar

• 454

  BarkerEFujimuraSFFademMBLandayALLevyJA. Immunologic abnormalities associated with chronic fatigue syndrome. Clin Infect Dis (1994) 18 Suppl 1:S136–41.

  • Google Scholar

• 455

  DeterrePBerthelierVBauvoisBDalloulASchuberFLundF. CD38 in t- and b-cell functions. Chem Immunol (2000) 75:146–68.

  • Google Scholar

• 456

  MorraMZubiaurMTerhorstCSanchoJMalavasiF. CD38 is functionally dependent on the TCR/CD3 complex in human t cells. FASEB J (1998) 12:581–92.

  • Google Scholar

• 457

  Baecher-AllanCWolfEHaflerDA. MHC class II expression identifies functionally distinct human regulatory t cells. J Immunol (2006) 176:4622–31.

  • Google Scholar

• 458

  ViallardJFBlancoPAndréMEtienneGLifermanFNeauDet al. CD8+HLA-DR+ t lymphocytes are increased in common variable immunodeficiency patients with impaired memory b-cell differentiation. Clin Immunol (2006) 119:51–8.

  • Google Scholar

• 459

  ViallardJFBloch-MichelCNeau-CransacMTaupinJLGarrigueSMiossecVet al. HLA-DR expression on lymphocyte subsets as a marker of disease activity in patients with systemic lupus erythematosus. Clin Exp Immunol (2001) 125:485–91.

  • Google Scholar

• 460

  HardcastleSLBrenuEWJohnstonSNguyenTHuthTWongNet al. Characterisation of cell functions and receptors in chronic fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME). BMC Immunol (2015) 16:35.

  • Google Scholar

• 461

  TheorellJBileviciute-LjungarITesiBSchlumsHJohnsgaardMSAsadi-AzarbaijaniBet al. Unperturbed cytotoxic lymphocyte phenotype and function in myalgic Encephalomyelitis/Chronic fatigue syndrome patients. Front Immunol (2017) 8.

  • Google Scholar

• 462

  GaoZFengYXuJLiangJ. T-cell exhaustion in immune-mediated inflammatory diseases: New implications for immunotherapy. Front Immunol 13 (2022).

  • Google Scholar

• 463

  CallenderLACarrollECBoberEAAkbarANSolitoEHensonSM. Mitochondrial mass governs the extent of human t cell senescence. Aging Cell (2020) 19:e13067.

  • Google Scholar

• 464

  HornigM. Can the light of immunometabolism cut through "brain fog"? J Clin Invest (2020) 130:1102–5.

  • Google Scholar

• 465

  BrenuEWvan DrielMLStainesDRAshtonKJRamosSBKeaneJet al. Immunological abnormalities as potential biomarkers in chronic fatigue Syndrome/Myalgic encephalomyelitis. J Transl Med (2011) 9:81.

  • Google Scholar

• 466

  CurriuMCarrilloJMassanellaMRigauJAlegreJPuigJet al. And t-cell phenotype and function in patients suffering from chronic fatigue syndrome. J Transl Med (2013) 11:68.

  • Google Scholar

• 467

  RamosSBrenuEBroadleySKwiatekRNgJNguyenTet al. Natural killer t and γδ t cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison. Asian Pac J Allergy Immunol (2016) 34:300–5.

  • Google Scholar

• 468

  GroblerCMaphumuloSCGrobbelaarLMBredenkampJCLaubscherGJLourensPJet al. Covid-19: The rollercoaster of Fibrin(Ogen), d-dimer, von willebrand factor, p-selectin and their interactions with endothelial cells, platelets and erythrocytes. Int J Mol Sci (2020) 21.

  • Google Scholar

• 469

  KondlkováKVokurkováDKrejsekJBorskáLFialaZCtiradA. Regulatory t cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Med (Hradec Kralove) (2010) 53:73–7.

  • Google Scholar

• 470

  BrenuEWHardcastleSLAtkinsonGMvan DrielMLKreijkamp-KaspersSAshtonKJet al. Natural killer cells in patients with severe chronic fatigue syndrome. Auto Immun Highlights (2013) 4:69–80.

  • Google Scholar

• 471

  CaligiuriMMurrayCBuchwaldDLevineHCheneyPPetersonDet al. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol (1987) 139:3306–13.

  • Google Scholar

• 472

  FletcherMAZengXRMaherKLevisSHurwitzBAntoniMet al. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PloS One (2010) 5:e10817.

  • Google Scholar

• 473

  NatelsonBHHaghighiMHPonzioNM. Evidence for the presence of immune dysfunction in chronic fatigue syndrome. Clin Diagn Lab Immunol (2002) 9:747–52.

  • Google Scholar

• 474

  RasaSNora-KrukleZHenningNEliassenEShikovaEHarrerTet al. Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Transl Med (2018) 16:268.

  • Google Scholar

• 475

  VivierETomaselloEBaratinMWalzerTUgoliniS. Functions of natural killer cells. Nat Immunol (2008) 9:503–10.

  • Google Scholar

• 476

  BrenuEWvan DrielMLStainesDRAshtonKJHardcastleSLKeaneJet al. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med (2012) 10:88.

  • Google Scholar

• 477

  Eaton-FitchNdu PreezSCabanasHStainesDMarshall-GradisnikS. A systematic review of natural killer cells profile and cytotoxic function in myalgic encephalomyelitis/chronic fatigue syndrome. Syst Rev (2019) 8:279.

  • Google Scholar

• 478

  BorishLSchmalingKDiClementiJDStreibJNegriJJonesJF. Chronic fatigue syndrome: identification of distinct subgroups on the basis of allergy and psychologic variables. J Allergy Clin Immunol (1998) 102:222–30.

  • Google Scholar

• 479

  CorbittMEaton-FitchNStainesDCabanasHMarshall-GradisnikS. A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID). BMC Neurol (2019) 19:207.

  • Google Scholar

• 480

  GiloteauxLO'NealACastro-MarreroJLevineSMHansonMR. Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study. J Transl Med (2020) 18:387.

  • Google Scholar

• 481

  GuptaSAggarwalSSeeDStarrA. Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome. J Psychiatr Res (1997) 31:149–56.

  • Google Scholar

• 482

  YangTYangYWangDLiCQuYGuoJet al. The clinical value of cytokines in chronic fatigue syndrome. J Trans Med (2019) 17:213.

  • Google Scholar

• 483

  BrenuEWBroadleySNguyenTJohnstonSRamosSStainesDet al. A preliminary comparative assessment of the role of CD8+ t cells in chronic fatigue Syndrome/Myalgic encephalomyelitis and multiple sclerosis. J Immunol Res (2016) 2016:9064529.

  • Google Scholar

• 484

  Cortes RiveraMMastronardiCSilva-AldanaCTArcos-BurgosMLidburyBA. Myalgic Encephalomyelitis/Chronic fatigue syndrome: A comprehensive review. Diagnostics (Basel) 9 (2019).

  • Google Scholar

• 485

  MandaranoAHMayaJGiloteauxLPetersonDLMaynardMGottschalkCGet al. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered t cell metabolism and cytokine associations. J Clin Invest (2020) 130:1491–505.

  • Google Scholar

• 486

  CurriuMCarrilloJMassanellaMRigauJAlegreJPuigJet al. and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome. J Transl Med. (2013) 11:68. doi: 10.1186/1479-5876-11-68

  • CrossRef
  • Google Scholar

• 487

  AscherioAMungerKL. EBV and autoimmunity. Epstein Barr Virus Volume 1: One Herpes Virus: Many Dis. (2015) 390:365–85. doi: 10.1007/978-3-319-22822-8_15

  • CrossRef
  • Google Scholar

• 488

  RichmanSMorrisMCBroderickGCraddockTJAKlimasNGFletcherMA. Pharmaceutical interventions in chronic fatigue syndrome: A literature-based commentary. Clin Ther. (2019) 41:798–805. doi: 10.1016/j.clinthera.2019.02.011

  • CrossRef
  • Google Scholar

• 489

  Carlo-StellaNBozziniSDe SilvestriASbarsiIPizzocheroCLorussoLet al. Molecular study of receptor for advanced glycation endproduct gene promoter and identification of specific HLA haplotypes possibly involved in chronic fatigue syndrome. Int J Immunopathol Pharmacol. (2009) 22:745–54. doi: 10.1177/039463200902200320

  • CrossRef
  • Google Scholar

• 490

  UnderhillJAMahalingamMPeakmanMWesselyS. Lack of association between HLA genotype and chronic fatigue syndrome. Eur J Immunogenet. (2001) 28:425–8. doi: 10.1046/j.1365-2370.2001.00235.x

  • CrossRef
  • Google Scholar

• 491

  KochiY. Genetics of autoimmune diseases: perspectives from genome-wide association studies. Int Immunol. (2016) 28:155–61. doi: 10.1093/intimm/dxw002

  • CrossRef
  • Google Scholar

• 492

  FrederiksenBLiuERomanosJSteckAYinXKroehlMet al. Investigation of the vitamin D receptor gene (VDR) and its interaction with protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2) on risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). J Steroid Biochem Mol Biol. (2013) 133:51–7. doi: 10.1016/j.jsbmb.2012.08.012

  • CrossRef
  • Google Scholar

• 493

  SigurdssonSNordmarkGGarnierSGrundbergEKwanTNilssonOet al. A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum Mol Genet. (2008) 17:2868–76. doi: 10.1093/hmg/ddn184

  • CrossRef
  • Google Scholar

• 494

  HirschfieldGMLiuXXuCLuYXieGLuYet al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. New Engl J Med. (2009) 360:2544–55. doi: 10.1056/NEJMoa0810440

  • CrossRef
  • Google Scholar

• 495

  TingW-HChienM-NLoF-SWangC-HHuangC-YLinC-Let al. Association of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene polymorphisms with autoimmune thyroid disease in children and adults: case-control study. PloS One. (2016) 11:e0154394. doi: 10.1371/journal.pone.0154394

  • CrossRef
  • Google Scholar

• 496

  RajeevanMSDimulescuIMurrayJFalkenbergVRUngerER. Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. Hum Immunol. (2015) 76:553–60. doi: 10.1016/j.humimm.2015.06.014

  • CrossRef
  • Google Scholar

• 497

  NillerHHWolfHAyEMinarovitsJ. Epigenetic dysregulation of epstein-barr virus latency and development of autoimmune disease. Epigenetic Contributions Autoimmune Dis. (2011) 711, 82–102. doi: 10.1007/978-1-4419-8216-2_7

  • CrossRef
  • Google Scholar

• 498

  ManianFA. Simultaneous measurement of antibodies to Epstein-Barr virus, human herpesvirus 6, herpes simplex virus types 1 and 2, and 14 enteroviruses in chronic fatigue syndrome: is there evidence of activation of a nonspecific polyclonal immune response? Clin Infect Dis. (1994) 19:448–53. doi: 10.1093/clinids/19.3.448

  • CrossRef
  • Google Scholar

• 499

  LoebelMEckeyMSotznyFHahnEBauerSGrabowskiPet al. Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray. PloS One. (2017) 12:e0179124. doi: 10.1371/journal.pone.0179124

  • CrossRef
  • Google Scholar

• 500

  LoebelMStrohscheinKGianniniCKoelschUBauerSDoebisCet al. Deficient EBV-specific B-and T-cell response in patients with chronic fatigue syndrome. PloS One. (2014) 9:e85387. doi: 10.1371/journal.pone.0085387

  • CrossRef
  • Google Scholar

• 501

  KerrJR. Epstein-barr virus induced gene-2 upregulation identifies a particular subtype of chronic fatigue syndrome/myalgic encephalomyelitis. Front Pediatr. (2019) 7:59. doi: 10.3389/fped.2019.00059

  • CrossRef
  • Google Scholar

• 502

  NishikaiMTomomatsuSHankinsRWTakagiSMiyachiKKosakaSet al. Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology. (2001) 40:806–10. doi: 10.1093/rheumatology/40.7.806

  • CrossRef
  • Google Scholar

• 503

  LoebelMGrabowskiPHeideckeHBauerSHanitschLGWittkeKet al. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. (2016) 52:32–9. doi: 10.1016/j.bbi.2015.09.013

  • CrossRef
  • Google Scholar

• 504

  TanakaSKuratsuneHHidakaYHakariyaYTatsumiK-ITakanoTet al. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med. (2003) 12:225–30. doi: 10.3892/ijmm

  • CrossRef
  • Google Scholar

• 505

  MikeczAVKonstantinovKBuchwaldDSGeraceLTanEM. High frequency of autoantibodies to insoluble cellular antigens in patients with chronic fatigue syndrome. Arthritis Rheumatism: Off J Am Coll Rheumatol. (1997) 40:295–305. doi: 10.1002/art.1780400215

  • CrossRef
  • Google Scholar

• 506

  Ortega-HernandezODCucciaMBozziniSBassiNMoscavitchSDiaz-GalloLMet al. Autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen class II alleles in chronic fatigue syndrome: are they associated with age at onset and specific symptoms? Ann New York Acad Sci. (2009) 1173:589–99. doi: 10.1111/j.1749-6632.2009.04802.x

  • CrossRef
  • Google Scholar

• 507

  De BeéckKOVermeerschPVerschuerenPWesthovensRMariënGBlockmansDet al. Antinuclear antibody detection by automated multiplex immunoassay in untreated patients at the time of diagnosis. Autoimmun Rev. (2012) 12:137–43. doi: 10.1016/j.autrev.2012.02.013

  • CrossRef
  • Google Scholar

• 508

  KleinRBergP. High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: evidence for a clinical entity of both disorders. Eur J Med Res. (1995) 1:21–6.

  • Google Scholar

• 509

  HokamaYEmpey-CamporaCHaraCHigaNSiuNLauRet al. Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic Ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins. J Clin Lab Anal. (2008) 22:99–105. doi: 10.1002/jcla.20217

  • CrossRef
  • Google Scholar

• 510

  HokamaYCamporaCEHaraCKuribayashiTLe HuynhDYabusakiK. Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome. J Clin Lab Anal. (2009) 23:210–2. doi: 10.1002/jcla.20325

  • CrossRef
  • Google Scholar

• 511

  KonstantinovKvon MikeczABuchwaldDJonesJGeraceLTanEM. Autoantibodies to nuclear envelope antigens in chronic fatigue syndrome. J Clin Invest. (1996) 98:1888–96. doi: 10.1172/JCI118990

  • CrossRef
  • Google Scholar

• 512

  Cabral-MarquesOMarquesAGiilLMDe VitoRRademacherJGüntherJet al. GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nat Commun. (2018) 9:5224. doi: 10.1038/s41467-018-07598-9

  • CrossRef
  • Google Scholar

• 513

  HartwigJSotznyFBauerSHeideckeHRiemekastenGDragunDet al. IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS. Brain Behavior Immun - Health. (2020) 3:100047. doi: 10.1016/j.bbih.2020.100047

  • CrossRef
  • Google Scholar

• 514

  MaesMMihaylovaIKuberaMLeunisJ-CTwiskFNMGeffardM. IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression. Metab Brain Dis. (2012) 27:415–23. doi: 10.1007/s11011-012-9316-8

  • CrossRef
  • Google Scholar

• 515

  ElfaitouriAHerrmannBBölin-WienerAWangYGottfriesC-GZachrissonOet al. Epitopes of microbial and human heat shock protein 60 and their recognition in myalgic encephalomyelitis. PloS One. (2013) 8:e81155. doi: 10.1371/journal.pone.0081155

  • CrossRef
  • Google Scholar

• 516

  VernonSDReevesWC. Evaluation of autoantibodies to common and neuronal cell antigens in Chronic Fatigue Syndrome. J Autoimmune Dis. (2005) 2:5. doi: 10.1186/1740-2557-2-5

  • CrossRef
  • Google Scholar

• 517

  MaesMMihaylovaILeunisJC. Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett. (2006) 27:615–21.

  • Google Scholar

• 518

  FasanoA. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Research. (2020) 9. doi: 10.12688/f1000research

  • CrossRef
  • Google Scholar

• 519

  MoisiniIDavidsonA. BAFF: a local and systemic target in autoimmune diseases. Clin Exp Immunol. (2009) 158:155–63. doi: 10.1111/j.1365-2249.2009.04007.x

  • CrossRef
  • Google Scholar

• 520

  MackayFSchneiderP. Cracking the BAFF code. Nat Rev Immunol. (2009) 9:491–502. doi: 10.1038/nri2572

  • CrossRef
  • Google Scholar

• 521

  Saulep-EastonDVincentFBQuahPSWeiATingSBCroceCMet al. The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells. Leukemia. (2016) 30:163–72. doi: 10.1038/leu.2015.174

  • CrossRef
  • Google Scholar

• 522

  HedgerMPde KretserDM. The activins and their binding protein, follistatin—diagnostic and therapeutic targets in inflammatory disease and fibrosis. Cytokine Growth factor Rev. (2013) 24:285–95. doi: 10.1016/j.cytogfr.2013.03.003

  • CrossRef
  • Google Scholar

• 523

  LidburyBAKitaBLewisDPHaywardSLudlowHHedgerMPet al. Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study. J Trans Med. (2017) 15:1–10. doi: 10.1186/s12967-017-1161-4

  • CrossRef
  • Google Scholar

• 524

  CoxBSAlharshawiKMena-PalomoILafuseWPArizaME. EBV/HHV-6A dUTPases contribute to myalgic encephalomyelitis/chronic fatigue syndrome pathophysiology by enhancing TFH cell differentiation and extrafollicular activities. JCI Insight. (2022) 7. doi: 10.1172/jci.insight.158193

  • CrossRef
  • Google Scholar

• 525

  SpolskiRLeonardWJ. Interleukin-21: a double-edged sword with therapeutic potential. Nat Rev Drug Discovery. (2014) 13:379–95. doi: 10.1038/nrd4296

  • CrossRef
  • Google Scholar

• 526

  CrottyS. T follicular helper cell biology: A decade of discovery and diseases. Immunity. (2019) 50:1132–48. doi: 10.1016/j.immuni.2019.04.011

  • CrossRef
  • Google Scholar

• 527

  ChenWTen DijkeP. Immunoregulation by members of the TGFβ superfamily. Nat Rev Immunol. (2016) 16:723–40. doi: 10.1038/nri.2016.112

  • CrossRef
  • Google Scholar

• 528

  ChangPPBarralPFitchJPratamaAMaCSKalliesAet al. Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat Immunol. (2011) 13:35–43. doi: 10.1038/ni.2166

  • CrossRef
  • Google Scholar

• 529

  SmithMBHaneyEMcDonaghMPappasMDaegesMWassonNet al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Internal Med. (2015) 162:841–50. doi: 10.7326/M15-0114

  • CrossRef
  • Google Scholar

• 530

  Castro-MarreroJSáez-FrancàsNSantilloDAlegreJ. Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome. Br J Pharmacol. (2017) 174:345–69. doi: 10.1111/bph.13702

  • CrossRef
  • Google Scholar

• 531

  KimDYLeeJSParkSYKimSJSonCG. Systematic review of randomised controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. (2020) 18:7. doi: 10.1186/s12967-019-02196-9

  • CrossRef
  • Google Scholar

• 532

  U.S. ME/CFS clinician coalition, diagnosing and treating myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). (U.S. ME/CFS CLinician Coalition) (2020).

  • Google Scholar

• 533

  CullinanJPhebyDFHArajaDBerkisUBrennaEde KorwinJDet al. Perceptions of european ME/CFS experts concerning knowledge and understanding of ME/CFS among primary care physicians in europe: A report from the european ME/CFS research network (EUROMENE). Medicina (Kaunas). (2021) 57. doi: 10.3390/medicina57030208

  • CrossRef
  • Google Scholar

• 534

  HngKNGeraghtyKPhebyDFH. An audit of UK hospital doctors’ Knowledge and experience of myalgic encephalomyelitis. Medicina (Kaunas). (2021) 57. doi: 10.3390/medicina57090885

  • CrossRef
  • Google Scholar

• 535

  McEvedyCPBeardAW. Concept of benign myalgic encephalomyelitis. Br Med J. (1970) 1:11–5. doi: 10.1136/bmj.1.5687.11

  • CrossRef
  • Google Scholar

• 536

  HooperM. Myalgic encephalomyelitis: a review with emphasis on key findings in biomedical research. J Clin Pathol. (2007) 60:466–71. doi: 10.1136/jcp.2006.042408

  • CrossRef
  • Google Scholar

• 537

  EvengårdBSchacterleRSKomaroffAL. Chronic fatigue syndrome: new insights and old ignorance. J Intern Med. (1999) 246:455–69. doi: 10.1046/j.1365-2796.1999.00513.x

  • CrossRef
  • Google Scholar

• 538

  DavidASWesselySPelosiAJ. Postviral fatigue syndrome: time for a new approach. Br Med J (Clin Res Ed). (1988) 296:696–9. doi: 10.1136/bmj.296.6623.696

  • CrossRef
  • Google Scholar

• 539

  StricklinASewellMAustadC. Objective measurement of personality variables in epidemic neuromyasthenia patients. S Afr Med J. (1990) 77:31–4.

  • Google Scholar

• 540

  American geriatrics society, american geriatrics society 2019 updated AGS beers criteria^® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. (2019) 67:674–94. doi: 10.1111/jgs.15767

  • CrossRef
  • Google Scholar

• 541

  National Institute for Health and Care Excellence - NICE, Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management (2007).

  • Google Scholar

• 542

  JasonLABrownMBrownAEvansMFloresSGrant-HollerEet al. Energy conservation/envelope theory interventions to help patients with myalgic encephalomyelitis/chronic fatigue syndrome. Fatigue. (2013) 1:27–42. doi: 10.1080/21641846.2012.733602

  • CrossRef
  • Google Scholar

• 543

  GeraghtyKHannMKurtevS. Myalgic encephalomyelitis/chronic fatigue syndrome patients’ reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: Analysis of a primary survey compared with secondary surveys. J Health Psychol. (2019) 24:1318–33. doi: 10.1177/1359105317726152

  • CrossRef
  • Google Scholar

• 544

  KindlonT. Reporting of harms associated with graded exercise therapy and cognitive behavioural therapy in myalgic encephalomyelitis/chronic fatigue syndrome. Bull IACFS/ME. (2011) 19:59–111.

  • Google Scholar

• 545

  Psychotherapy for major depressive disorder and generalised anxiety disorder: A health technology assessment. Ont Health Technol Assess Ser. (2017) 17:1–167.

  • Google Scholar

• 546

  ME Association. TRIAL BY ERROR: the troubling case of the PACE chronic fatigue syndrome study| investigation by david tuller (Accessed 21 October 2015).

  • Google Scholar

• 547

  WhitePDGoldsmithKAJohnsonALPottsLWalwynRDeCesareJCet al. Comparison of adaptive pacing therapy, cognitive behavior therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. (2011) 377:823–36. doi: 10.1016/S0140-6736(11)60096-2

  • CrossRef
  • Google Scholar

• 548

  WhitePDGoldsmithKJohnsonALChalderTSharpeM. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. (2013) 43:2227–35. doi: 10.1017/S0033291713000020

  • CrossRef
  • Google Scholar

• 549

  WilshireCEKindlonT. Response: Sharpe, Goldsmith and Chalder fail to restore confidence in the PACE trial findings. BMC Psychol. (2019) 7:19. doi: 10.1186/s40359-019-0296-x

  • CrossRef
  • Google Scholar

• 550

  WilshireCEKindlonTCourtneyRMattheesATullerDGeraghtyKet al. Rethinking the treatment of chronic fatigue syndrome-a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychol. (2018) 6:6. doi: 10.1186/s40359-018-0218-3

  • CrossRef
  • Google Scholar

• 551

  PhebyDSaffronL. Risk factors for severe ME/CFS. Biol Med. (2009) 1:50–74.

  • Google Scholar

• 552

  CampbellB. Pacing tutorial. In: ME/CFS and fibromyalgia self-help program. (USA: ME/CFS and Fibromyalgia Self-Help) (2020).

  • Google Scholar

• 553

  Visible, visible. (2024). Available at: https://www.makevisible.com

  • Google Scholar

• 554

  AaronLAHerrellRAshtonSBelcourtMSchmalingKGoldbergJet al. Comorbid clinical conditions in chronic fatigue: a co-twin control study. J Gen Intern Med. (2001) 16:24–31. doi: 10.1046/j.1525-1497.2001.03419.x

  • CrossRef
  • Google Scholar

• 555

  NatelsonBH. Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: definitions, similarities, and differences. Clin Ther. (2019) 41:612–8. doi: 10.1016/j.clinthera.2018.12.016

  • CrossRef
  • Google Scholar

• 556

  GoldenbergDLSimmsRWGeigerAKomaroffAL. High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice. Arthritis Rheum. (1990) 33:381–7. doi: 10.1002/art.1780330311

  • CrossRef
  • Google Scholar

• 557

  McKayPGWalkerHMartinCRFlemingM. Exploratory study into the relationship between the symptoms of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and fibromyalgia (FM) using a quasiexperimental design. BMJ Open. (2021) 11:e041947. doi: 10.1136/bmjopen-2020-041947

  • CrossRef
  • Google Scholar

• 558

  ReynoldsGKLewisDPRichardsonAMLidburyBA. Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. J Intern Med. (2014) 275:409–17. doi: 10.1111/joim.12161

  • CrossRef
  • Google Scholar

• 559

  HoadASpickettGElliottJNewtonJ. Postural orthostatic tachycardia syndrome is an under-recognised condition in chronic fatigue syndrome. Qjm. (2008) 101:961–5. doi: 10.1093/qjmed/hcn123

  • CrossRef
  • Google Scholar

• 560

  JonesJFNicholsonANisenbaumRPapanicolaouDASolomonLBonevaRet al. Orthostatic instability in a population-based study of chronic fatigue syndrome. Am J Med. (2005) 118:1415. doi: 10.1016/j.amjmed.2005.06.013

  • CrossRef
  • Google Scholar

• 561

  DahanSTomljenovicLShoenfeldY. Postural Orthostatic Tachycardia Syndrome (POTS)–A novel member of the autoimmune family. Lupus. (2016) 25:339–42. doi: 10.1177/0961203316629558

  • CrossRef
  • Google Scholar

• 562

  ShanksLJasonLAEvansMBrownA. Cognitive impairments associated with CFS and POTS. Front Physiol. (2013) 4:113. doi: 10.3389/fphys.2013.00113

  • CrossRef
  • Google Scholar

• 563

  RoerinkMELendersJWSchmitsICPistoriusAMSmitJWKnoopHet al. Postural orthostatic tachycardia is not a useful diagnostic marker for chronic fatigue syndrome. J Intern Med. (2017) 281:179–88. doi: 10.1111/joim.12564

  • CrossRef
  • Google Scholar

• 564

  MitchellWM. Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Expert Rev Clin Pharmacol (2016) 9:755–70.

  • Google Scholar

• 565

  ZarlingJMSchlaisJEskraLGreeneJJTs'oPOCarterWA. Augmentation of human natural killer cell activity by polyinosinic acid-polycytidylic acid and its nontoxic mismatched analogues. J Immunol (1980) 124:1852–7.

  • Google Scholar

• 566

  KimJYangGKimYKimJHaJ. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med (2016) 48:e224–4.

  • Google Scholar

• 567

  ToogoodPLClauwDJPhadkeSHoffmanD. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from? Pharmacol Res (2021) 165:105465.

  • Google Scholar

• 568

  ScheibenbogenCLoebelMFreitagHKruegerABauerSAntelmannMet al. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PloS One (2018) 13:e0193672.

  • Google Scholar

• 569

  ProalADAlbertPJBlaneyGPLindsethIABenediktssonCet al. Immunostimulation in the era of the metagenome. Cell Mol Immunol (2011) 8:213–25.

  • Google Scholar

• 570

  TölleMFreitagHAntelmannMHartwigJSchuchardtMvan der Giet,Met al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption. J Clin Med (2020) 9.

  • Google Scholar

• 571

  RekelandIGFossåALandeAKtoridou-ValenISørlandKHolsenMet al. Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study. Front Med (Lausanne) (2020) 7:162.

  • Google Scholar

• 572

  JainSKParsanathanRAchariAEKanikarla-MariePBocchiniJAJr.. Glutathione Stimulates Vitamin D Regulatory and Glucose-Metabolism Genes, Lowers Oxidative Stress and Inflammation, and Increases 25-Hydroxy-Vitamin D Levels in Blood: A Novel Approach to Treat 25-Hydroxyvitamin D Deficiency. Antioxid Redox Signal (2018) 29:1792–807.

  • Google Scholar

• 573

  IgnarroLJ. Physiology and pathophysiology of nitric oxide. Kidney Int Suppl (1996) 55:S2–5.

  • Google Scholar

• 574

  KaiserJD. A prospective, proof-of-concept investigation of KPAX002 in chronic fatigue syndrome. Int J Clin Exp Med (2015) 8:11064–74.

  • Google Scholar

• 575

  MontoyaJGAndersonJNAdolphsDLBatemanLKlimasNGLevineSMet al. KPAX 002 as a treatment for Myalgic Encephalomyelitis / Chronic Fatigue Syndrome ( ME / CFS ) : a prospective , randomized trial. (2018).

  • Google Scholar

• 576

  Castro-MarreroJSáez-FrancàsNSegundoMJCalvoNFaroMAlisteLet al. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. Clin Nutr (2016) 35:826–34.

  • Google Scholar

• 577

  Castro-MarreroJCorderoMDSegundoMJSáez-FrancàsNCalvoNRomán-MaloLet al. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal (2015) 22:679–85.

  • Google Scholar

• 578

  ForsythLMPreussHGMacDowellALChiazzeLJr.BirkmayerGDBellantiJA. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol (1999) 82:185–91.

  • Google Scholar

• 579

  MaksoudRBalinasCHoldenSCabanasHStainesDMarshall-GradisnikS. A systematic review of nutraceutical interventions for mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med (2021) 19:81.

  • Google Scholar

• 580

  FlugeØBrulandORisaKStorsteinAKristoffersenEKSapkotaDet al. Benefit from b-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. a double-blind and placebo-controlled study. PloS One (2011) 6(10):e26358. doi: 10.1371/journal.pone.0026358

  • CrossRef
  • Google Scholar

• 581

  AdamowiczJLCaikauskaiteIFriedbergF. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res. (2014) 23:2407–16. doi: 10.1007/s11136-014-0705-9

  • CrossRef
  • Google Scholar

• 582

  DevendorfARJacksonCTSunnquistM. Defining and measuring recovery from myalgic encephalomyelitis and chronic fatigue syndrome: the physician perspective. Disabil Rehabil. (2019) 41:158–65. doi: 10.1080/09638288.2017.1383518

  • CrossRef
  • Google Scholar

• 583

  KoenigJESporAScalfoneNFrickerADStombaughJKnightRet al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U.S.A. (2011) 108 Suppl 1:4578–85. doi: 10.1073/pnas.1000081107

  • CrossRef
  • Google Scholar

• 584

  TamburiniSShenNWuHCClementeJC. The microbiome in early life: implications for health outcomes. Nat Med. (2016) 22:713–22. doi: 10.1038/nm.4142

  • CrossRef
  • Google Scholar

• 585

  PalmerCBikEMDiGiulioDBRelmanDABrownPO. Development of the human infant intestinal microbiota. PloS Biol. (2007) 5:e177. doi: 10.1371/journal.pbio.0050177

  • CrossRef
  • Google Scholar

• 586

  DecodeME. (2023). Available at: https://www.decodeme.org.uk

  • Google Scholar

• 587

  ShanZYBarndenLRKwiatekRABhutaSHermensDFLagopoulosJ. Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review. J Transl Med. (2020) 18:335. doi: 10.1186/s12967-020-02506-6

  • CrossRef
  • Google Scholar

• 588

  FriedmanKJMurovskaMPhebyDFHZalewskiP. Our evolving understanding of ME/CFS. Medicina (Kaunas) 57. (2021). doi: 10.3390/medicina57030200

  • CrossRef
  • Google Scholar

• 589

  NaculLAuthierFJScheibenbogenCLorussoLHellandIBMartinJAet al. European network on myalgic encephalomyelitis/chronic fatigue syndrome (EUROMENE): expert consensus on the diagnosis, service provision, and care of people with ME/CFS in europe. Medicina (Kaunas) 57. (2021). doi: 10.3390/medicina57050510

  • CrossRef
  • Google Scholar

• 590

  Open Medicine Foundation

• 591

  The Charité Fatigue Center

• 592

  WE&ME Foundation

• 593

  TysonSStanleyKGronlundTALearySEmmans DeanMDransfieldCet al. Research priorities for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): the results of a James Lind alliance priority setting exercise. Fatigue: Biomedicine Health Behav. (2022) 10:200–11. doi: 10.1080/21641846.2022.2124775

  • CrossRef
  • Google Scholar