Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an incapacitating chronic disease that dramatically compromise the life quality. The CFS/ME pathogenesis is multifactorial, and it is believed that immunological, metabolic and environmental factors play a role.
It is well documented an increased activity of Human endogenous retroviruses (HERVs) from different families in autoimmune and neurological diseases, making these elements good candidates for biomarkers or even triggers for such diseases. Here the expression of Endogenous retroviruses K and W (HERV-K and HERV-W) was determined in blood from moderately and severely affected ME/CFS patients.
HERV-K was overexpressed only in moderately affected individuals and HERV-W showed no difference. This is the first report about HERV-K differential expression in moderate ME/CFS.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology that is recognized by the World Health Organization (WHO) and the United States Center for Disease Control and Prevention (US CDC) as a disorder of the brain. The disease predominantly affects adults, with a peak age of onset of between 20 and 45 years with a female to male ratio of 3:1.
Although the clinical features of the disease have been well established within diagnostic criteria, the diagnosis of ME/CFS is still of exclusion, meaning that other medical conditions must be ruled out. The pathophysiological mechanisms are unclear but the neuro-immuno-endocrinological pattern of CFS patients gleaned from various studies indicates that these three pillars may be the key point to understand the complexity of the disease.
At the moment, there are no specific pharmacological therapies to treat the disease, but several studies’ aims and therapeutic approaches have been described in order to benefit patients’ prognosis, symptomatology relief, and the recovery of pre-existing function. This review presents a pathophysiological approach to understanding the essential concepts of ME/CFS, with an emphasis on the population, clinical, and genetic concepts associated with ME/CFS.
Excerpt from the Discussion:
The first clinicians to describe the syndrome, as reviewed earlier, immediately associated the disease with an ongoing infection. Nowadays, with a significant core of research, it is known that the disease has its pathophysiological sustenance in “three pillars” that continuously interact with each other: the immune system, the nervous system, and the neuroendocrine network. Table 1 offers a brief summary of the main features of the tissues involved in the “three pillars” hypothesis.
As can be seen in Table 3, current therapeutic strategies target several elements of the proposed neuro-immunoendocrine network, which also supports the “three pillars” hypothesis that we are discussing in this review. The immune system is involved in modulating neural plasticity, learning, and memory, although the precise link between these two seemingly distinct systems was, until recently, unclear [54]. The connection may be explained by the coevolution of the nervous and immune systems, as the two systems share mechanisms of stimulation, cell communication and signaling, gene regulation, and supracellular organization. The immune system supports the central nervous system (CNS) and aids functional recovery by facilitating the renewal, migration and cell lineage specification of neural progenitor cells [221].
The immune system is involved in the stress response, since stress activates the immune system, leading to peripheral inflammation that may ultimately contribute to the onset of a part of the symptomatology of the disease [222]. Indeed, stress has been shown to be an essential predisposing factor in the development of several neurodegenerative and psychiatric disorders [223]. The hypothalamic–pituitary–adrenal (HPA) axis and the systemic sympatho-adrenomedullary (SAM) system are essential modulators of stress response systems [224]. The HPA axis is an endocrine pathway that regulates standard stress response and merges with the immune system to maintain homeostasis [138,139].
Therefore, stress stimulates the release of glucocorticoids, particularly cortisol, which is able to cross the BBB and alter the transcription of proteins in the brain [225]. Glucocorticoids bind to the glucocorticoid receptor (GR), resulting in disassociation from the heat-shock protein, and promoting a structural change of the receptor that enables the glucocorticoid-GR complex to enter the nucleus. The glucocorticoid-GR complex binds to the glucocorticoid response element on the DNA, resulting in the activation of transcription of immune-mediator genes, among others [223,226]. Therefore, stress hormones, such as cortisol, have the ability to regulate the immune system.
However, HPA is not the only neuroendocrinological network that can interact with the immune system. The SAM is also activated by stress, leading to the release of catecholamines (e.g., epinephrine and norepinephrine) in the adrenal medulla in response to stress [134,227]. Catecholamines have been found to regulate the synthesis of immune system mediators through β-adrenergic receptor stimulation [226], suggesting an alternative pathway that links the neuroendocrine and immunological systems.
ME/CFS patients show heightened negative feedback inhibition of the HPA axis, which is associated with hypocortisolism and heightened GR sensitivity [224].
As a result, patients with ME/CFS often show heightened immune responses owing to the combined effects of chronic stress with activated microglia [130,223] and increased HPA-axis sensitivity [224]. The HPA axis has been of great importance for the understanding of the pathophysiology of the disease, since the consequences of its alteration, such as hypocortisolism, have allowed us to understand the persistence of an altered immune status, the high risk of infections and the generation of humoral autoreactivity.
Although the metabolic sphere is not part of the aetiopathological pillars of the disease, it is clear that it is a physiological aspect compromised in patients with ME/CSF.
The dysregulation of the energetic metabolism can be understood as the tip of the iceberg, which will trigger the symptomatology experienced by the patient. However, the etiology of this metabolic imbalance in ME/CSF has not yet been understood, which is most likely because it is a pathological process that is the product of complex multisystemic interactions. Studies on metabolism and CFS suggest irregularities in energy metabolism, amino acid metabolism, nucleotide metabolism, nitrogen metabolism, hormone metabolism, and oxidative stress metabolism [228,229].
The overwhelming body of evidence suggests an oxidative environment with the minimal utilization of mitochondria for efficient energy production, leading to thoughts of some type of etiology in this organelle, but as we have seen previously, apparently the mitochondria are affected with the course of the disease [230]. As well as throughout the review, more studies are needed to understand which is the metabolic pathway that is first affected or which is the most altered in order to understand where to direct the etiological search in this complicated disease.
Introduction We investigated whether depressive symptoms at ages 9-13 years were associated with chronic disabling fatigue (CDF) at age 16 among children in the Avon Longitudinal Study of Parents & Children (ALSPAC) birth cohort.
Methods
Depressive symptoms at ages 9, 10, 11, 12, and 13 years were defined as a child- or parent-completed Short Mood and Feelings Questionnaire (SMFQ) score ≥11 (range 0-26). SMFQ score was also analysed as a continuous exposure. Chronic disabling fatigue at 16 was defined as fatigue of ≥6 months’ but <5 years’ duration which prevented school attendance or activities, for which other causes were not identified, and with a Chalder Fatigue Questionnaire score ≥19. Logistic regression was used with multiple imputation to correct for missing data bias. We performed sensitivity analyses in which children who had CDF and depressive symptoms at age 16 were reclassified as not having CDF.
Results
In fully adjusted models using imputed data (N = 13,978), depressive symptoms at ages 9, 11, and 13 years were associated with 2- to 3-fold higher odds of CDF at age 16. Each one-point increase in SMFQ score at ages 9, 10, 11, 12, and 13 years was associated with 6-11% higher odds of CDF at age 16. Depressive symptoms and continuous SMFQ scores at each age were not associated with CDF if the outcome was reclassified to exclude children with comorbid depressive symptoms at age 16.
Conclusions
Depressive symptoms at ages 9-13 were associated with chronic disabling fatigue at age 16, but causality is not certain.
Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac disease, chronic fatigue syndrome, and rheumatoid arthritis.
Fatigue is multi-faceted and broadly defined, which makes understanding the cause of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases. In general, fatigue is defined by debilitating periods of exhaustion that interfere with normal activities. The severity and duration of fatigue episodes vary, but fatigue can cause difficulty for even simple tasks like climbing stairs or crossing the room.
The exact mechanisms of fatigue are not well-understood, perhaps due to its broad definition. Nevertheless, physiological processes known to play a role in fatigue include oxygen/nutrient supply, metabolism, mood, motivation, and sleepiness—all which are affected by inflammation. Additionally, an important contributing element to fatigue is the central nervous system—a region impacted either directly or indirectly in numerous autoimmune and related disorders.
This review describes how inflammation and the central nervous system contribute to fatigue and suggests potential mechanisms involved in fatigue that are likely exhibited in autoimmune and related diseases.
Future Directions
There are several areas of research and logistics that need to be established to understand the exact mechanisms of fatigue and sleep in autoimmune diseases. First, a detailed description of particular types of fatigue needs to be established in the clinic. This can be achieved, in part, with more precise medical coding. Second, there needs to be standardized questionnaires and diagnostic tests that can more precisely indicate the determents observed from fatigue. This will provide insight into the types of fatigue that are observed with the pathogenesis of the autoimmune disorders.
Understanding the neurocircuitry of fatigue and its relationship between inflammation and autoimmune diseases is also needed. This area can aid in understanding the manifestation of types and severity of fatigue found in autoimmune patients. Since inflammation and metabolism are implicated in fatigue and impairments are found in these in autoimmune disorders, a detailed understating of the mechanisms of these systems, unique cells, and brain areas are lacking in autoimmune research.
More information on interactions between circadian timing and sleep/wake state or sleep loss, alterations in neuronal activity, and normal daily functioning that affect fatigue is required. And there needs to be a better understanding of the relationship between the vagal afferents in modulating brain inflammation to induce fatigue is needed. More research is also necessary for understanding the relationship between vasohemodynamics and fatigue in autoimmune disease.
Additionally, several autoimmune diseases are associated with disproportionately greater incidence and disease severity in particular genders and little information is known regarding the relationship of fatigue with these gender differences (373). The relationship of gender to fatigue in autoimmune disease should be a topic for future research.
An autoimmune disease involves multiple interactions between genetics and environmental factors. Most autoimmune-related disorders are more prevalent in monozygotic twins vs. dizygotic twins or siblings, indicating the involvement of genetics in disease development. Furthermore, genome wide association studies (GWAS) have found several genetic loci and small nucleotide polymorphisms that are associated with specific autoimmune disease prevalence.
Interestingly, proteins encoded by genes that are involved in inflammatory mechanisms including NF-κB, apoptosis, Toll-like receptor, and immune complexes are described in autoimmune and related disorders. Nevertheless, a number of autoimmune diseases exhibit similar genetic modifications, which likely contributes to the higher incidence of multiple autoimmune diseases found in individuals with autoimmune disorders and potentially similar disease characteristics including fatigue. Indeed, larger data sets (i.e., >10,000 individuals) are finding new associations of inflammatory mechanism I with impairments in respiratory function and sleep (374). Several inflammatory gene small nucleotide polymorphisms have been implicated in fatigue including TNF-α, IL-1β, IL-6, and IFN-γ (375).
Nevertheless, a high amount of the heritability of the genetics behind autoimmune and related disorders remains unexplained. In recent years, researchers, agencies, and governments, such as the British Biobank, Trans-Omics for Precision Medicine (TOPMED), and the Million Veteran Program have begun assembling very large sample populations that are giving enough statistical power to unmask genetic links between diseases.
Conclusion
In summary, fatigue is a major early finding in individuals with autoimmune diseases, and inflammation is a contributing factor relating to this impairment, one that affects the ability of people to perform daily activities, work, and thus their overall well-being. Recent research reveals a relationship between types of fatigue and certain brain areas, cell types, and phenotypes that mediate the symptoms observed.
In addition, inflammatory molecules that are enhanced in the periphery with specific types of autoimmune disease can alter brain inflammation and neurocircuitry affecting fatigue. Consequently, immunomodulatory agents and drugs targeting inflammatory pathways could serve to treat fatigue occurring in autoimmune and related diseases. Understanding the mechanisms behind fatigue will not only aid individuals with autoimmune diseases but could also benefit transplant recipients, cancer patients, and infectious disease patients who experience debilitating fatigue
The mitochondrial energy score (MES) protocol, developed by the Myhill group, is marketed as a diagnostic test for chronic fatigue syndrome/Myalgic Encephalomyelitis (CFS/ME). This study assessed the reliability and reproducibility of the test, currently provided by private clinics, to assess its potential to be developed as an NHS accredited laboratory test. We replicated the MES protocol using neutrophils and peripheral blood mononuclear cells (PBMCs) from CFS/ME patients (10) and healthy controls (13). The protocol was then repeated in PBMCs and neutrophils from healthy controls to investigate the effect of delayed sample processing time used by the Myhill group.
Experiments using the established protocol showed no differences between CFS/ME patients and healthy controls in any of the components of the MES (p ≥ 0.059). Delaying blood sample processing by 24 hours (well within the 72 hour time frame quoted by the Myhill group) significantly altered many of the parameters used to calculate the MES in both neutrophils and PBMCs. The MES test does not have the reliability and reproducibility required of a diagnostic test and therefore should not currently be offered as a diagnostic test for CFS/ME. The differences observed by the Myhill group may be down to differences in sample processing time between cohorts.
Discussion
Given the evidence presented here, we advise that the MES test should not be used as a diagnostic test in its current form as in this study shows there to be no differences between CFS/ME and control results when the MES protocol was followed using fresh blood samples. This is contrary to results from the group who devised the test and offer it to patients.
We explored the impact of delayed sample processing on blood glucose concentration in the collection tube as a possible explanation for the discrepancies in results between our group and the Myhill group. As expected with such high cell numbers the glucose rapidly dropped as the cells utilized the glucose. In addition the neutrophil component on FACS analysis in the white cell fraction showed differences in size and granularity between the 1 hr and 24 hr fractions suggestive of altered properties. Having taken into account a 24 hour delay between blood collection and cell isolation, we have shown decreases in ATP parameters in control cells similar to those seen by the Myhill group in the CFS/ME patients. We suggest that it is potentially the delay between sample collection and cell isolation that is causing the decrease in mitochondrial function previously reported in CFS/ME patients.
While this study used relatively small samples sizes compared with the original study, abnormalities in CFS/ME patients should be reproducible even in small sample sizes given the current use of this test for diagnostic purposes.
The Myhill group have recently altered their protocol to use PBMCs instead of neutrophils, however, this research has not been published and we have no information on the control ranges used and whether they were developed from blood samples processed over 24 hrs. The CFS/ME PBMC study by Tomas et al. did show the utility of using PBMC using the Seahorse extracellular flux analyser to study energetics3. However, the sudden switch to using PBMCs for the MES protocol appears to be as a result of criticism over the use of neutrophils rather than being an evidence lead change. There has been no data published from the Myhill group regarding the suitability of PBMCs with their previously established protocol, or any publication of results with the new cell type. After a diagnosis of CFS/ME is made using the MES test, patients are subsequently sold supplements in order to treat their CFS/ME, despite there being no placebo-controlled trial to show their effectiveness. The first peer-reviewed publication regarding the MES test from the Myhill group came after they had already been using the test and supplement regime with CFS/ME patients despite there being no published evidenced of the effectiveness, reliability, or reproducibility of the test. Additionally, the MES test has not been conducted using other patient groups with fatigue as a core symptom, therefore its specificity for CFS/ME has not been confirmed.
If energetic dysfunction is to be used as a marker of CFS/ME its exact role in the condition needs to be better understood including studying energetic dysfunction in other fatigue groups. Only when we have clearer understanding of the disease process and knowledge of specific factors shown to be different in CFS/ME should we consider developing a diagnostic test to aid in treatment strategies and determining outcome in clinical trials.
Clinicians approached by patients with results from the MES test should be advised to interpret the results with caution, while patients considering paying for the test should be advised of the lack of supporting scientific evidence. The test in its current form does not have the reliability or reproducibility required of a diagnostic test and therefore should not be offered by the NHS or private clinics as a diagnostic test for CFS/ME. Other tests of energetic dysfunction could be developed using the seahorse extracellular flux assay but more research is required as to the meaning of the results in the aetiology of CFS/ME before a test using this approach should be developed.
Responding to criticism of their mitochondrial test Myhill & McLaren emphasize that the test has “never been presented as a diagnostic test for CFS/ME.” They query whether the researchers did a true replication as they had offered to do a comparison test in their labs on the same samples but the offer wasn’t accepted. Regarding the technical details, Dr McLaren says he finds it strange that no significant differences were found between fresh & frozen cells, which is at odds with what he & other scientists have found while exploring the test.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk.
Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible ! cure.
A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common.
A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation.
This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.
Objectives
To describe the extent to which irritable bowel syndrome (IBS), fibromyalgia syndrome (FMS), and chronic fatigue syndrome (CFS) exhibit symptom overlap, and to validate a patient-derived, generic symptom questionnaire.
Methods A patient-derived 61-item symptom-frequency questionnaire was completed by participants recruited through IBS, FMS and CFS self-help websites. Principal axis factor analysis with oblimin rotation was performed separately for those reporting an IBS, FMS or CFS diagnosis.
Results
Questionnaires were completed by 1751 participants of whom 851 reported more than one of the three diagnoses. Stomach pain on at least a weekly basis was reported by 79% of IBS, 52% of FMS, and 43% of CFS single diagnosis participants. Pain increasing the day after activity was reported by 32% of IBS, 94% of FMS, and 85% of CFS single diagnosis participants. Waking still tired at least once weekly was reported by 75% of IBS, 97% of FMS, and 95% of CFS single diagnosis participants.
Exploratory factor analysis produced consistent results across all three diagnostic groups, the 61 items loading on 12 correlated factors with a single higher order factor on which all items loaded. Frequency analysis led to the rejection of one item (cold sores on or near lips), and freeform reporting by participants of additional symptoms identified an additional five, namely, restless legs, hair loss/brittle hair/thinning, dizziness/balance problems, blurred vision and urination problems.
Conclusions
IBS, FMS and CFS are polysymptomatic spectrum disorders with a wide range of overlapping symptoms, many of which are unrelated to diagnostic criteria. Frequency analysis and factor analysis confirm the validity of using the same questionnaire across different diagnostic categories. The 65-item general symptom questionnaire (GSQ-65) is a valid generic symptom scale suitable for assessing the many different symptoms of people with IBS, FMS and CFS.
Lola Brandrick, 13, from Swansea, is crippled by pain and is constantly exhausted
While all her school mates are out enjoying their summer holidays, poor Lola Brandrick can only dream of joining them.
The 13-year-old is confined to her bed, constantly exhausted and crippled by widespread pain due to a condition which continues to puzzle many doctors.
Even the smallest of tasks can have a devastating impact on the teenager’s energy levels for days, weeks or even months afterwards.
But ever since she was diagnosed with myalgic encephalomyelitis (ME) at the age of seven her family have fought to get her the care and support she desperately needs.
“Having to battle all the time just to be believed has been heartbreaking,” said her mum Victoria Lewis, 45, a fitness instructor and mum-of-two from Swansea.
It is well documented an increased activity of Human endogenous retroviruses (HERVs) from different families in autoimmune and neurological diseases, making these elements good candidates for biomarkers or even triggers for such diseases. Here the expression of Endogenous retroviruses K and W (HERV-K and HERV-W) was determined in blood from moderately and severely affected ME/CFS patients.
Stonebird – the lived experience of severe ME
