Another dollar, another day, another set of slides for Swiss Re

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Research requires funds and universities have overhead costs. The contributions of the Wessely School to research on ME/CFS are described in earlier posts. Here I start a series of posts on the funding sources of the universities involved.

Professor Sir Simon Wessely is the Regius Professor of Psychiatry, Director of King’s Centre for Military Health Research and, until recently, President, Royal Society of Medicine, 2017-2020.

Sir Simon Wessely is an eclectic presenter who taps effortlessly into a large store of knowledge from science, literature and the arts. He is a strategic thinker, who chooses his words carefully and deliberately. On this occasion, his topic is: “Everything you always wanted to know about mental health but were afraid to ask”.

Sir Simon is on home turf, an easy wicket on which to play smooth, well-timed strokes, with plenty of panache. No beating around the bush, Sir Simon’s first slide goes straight to the point: his competing interests. Here I quote directly from Sir Simon’s Swiss Re slide:

Competing interests


• Lots of funding from UK Research Councils, Wellcome, medical, military and veterans charities, UK Ministry of Defence and US Departments of Defense.


• Never had a penny from Pharma

• But frankly, my university will take money from anyone provided it comes with overheads.

Really? Can this be true?

Well, erm, yes, it is. In a later post, I will list a few specific funding sources.

A Significant Figure

In case it had escaped our attention, Sir Simon’s next slide shows a glimpse of the high circles he moves in.

A photo of a meeting with Mrs Theresa May, UK Prime Minister 2016-19.

Global Burden of Disease

The following slide turns to the meat of the presentation, mental health, and the huge global burden of disease, especially neuropsychiatric disease:

Medical Unexplained Symptoms

Curiously absent from Sir Simon’s slide is the category of Medical Unexplained Symptoms. According to the Royal Society of Psychiatrists:

  • About 1 in 4 people who see their GP have such symptoms. 
  • In a neurological outpatient setting, it is 1 in 3 patients or more

Stress is mentioned, insecurity, smoking, drinking, drugs, self-harm, internet abuse, almost everything to do with mental health, but nothing about MUS.

Skipping over 30 slides, available here – until they are taken down – Sir Simon finishes as he started, with humour and panache. Slide 34:

WHY I NEVER GIVE ADVICE

Then, slide 35:

BUT IF I DID…


• Never neglect the co morbidities
• Please don’t encourage anything that gives us more labels/diagnoses

• Be careful with your language – it can influence for good and ill

Sir Simon draws to a close with slide 36’s

Poetic Ending

“Who in the rainbow can draw the line where the violet tint ends and the orange tint begins? Distinctly we see the difference of the colors, but where exactly does the one first blendingly enter into the other? So with sanity and insanity. In pronounced cases there is no question about them. But in some supposed cases, in various degrees supposedly less pronounced, to draw the exact line of demarcation few will
undertake tho’ for a fee some professional experts will. There is nothing namable but that some men will undertake to do it for pay.”


“Billy Budd”, Herman Melville. 1888

I will return to this interesting conclusion later.

Dog whistle medicine and disability denial

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Here I review the corporate connections of the Wessely School with the insurance industry. The picture featured above shows the cover of a book edited by Peter Halligan and Mansel Alyward alongside a similar cover from the UnumProvident annual report of 2002.

Imaginary conversation

Imagine the conversation, which must have gone something like this:

Unum executive: Hi, how are you Mansel?

Aylward: Nor bad, thank you, I think I’ve got my ducks in a row with the university and the department.

Unum exec: Oh, great, your funding applications are being given serious attention.

Aylward: That’s wonderful, is there anything more I can do in return?

Unum exec: Well, yes, please keep plugging that biopsychosocial model thingy. Would be very good for our customers and, umm, well, yes, the profit margins of the company.

Aylward: Well, yes, sure, that’s exactly what we’re doing. We’re full steam ahead on it at the DWP also. We’ve got a new book about it coming out very soon.

Unum exec: Great. How about the book cover? Can you make it the same as our 2002 annual report?

Aylward: Well, yes, I’ll have to check with the publisher, of course, but I’m sure we can manage something quite similar.

Unum: This is why I like working with you guys, you are so cooperative.

Aylward: The feeling is mutual. Did you say the cheque’s in the post?

2002 Report by UnumProvident (on left} and book edited by Halligan and Aylward

———————————————————

Dogwhistle medicine

There’s nothing like a cartoon to get your point across. Here’s one chosen by Sir Mansel.

This picture is a favourite slide of inner circle member, Mansel Alyward, in a talk about disability medicine.

Another of Sir Mansell’s slides suggests the existence of strong scientific evidence that “we could reduce sickness absence due to common health problems by 30-50%, reduce number going on to chronic incapacity by 30-50% and, in principle, by much more” (Aylward, 2005).  

In Aylward’s own words lies the policy agenda for Unum, DWP, and the Wessely School all rolled into one:

‘Get people on sickness benefits back to work as quickly as possible’.

And if you can’t get them back to work, make sure their diagnosis is mental health not physical health.”

That’s the Holy Grail, a quick sharp shock (no pun intented) of GET and CBT, or no insurance payments for the rest of your unemployed life.

Under the imprint of the Royal Society of Medicine, Waddell and Aylward (2009) applied this approach in a comprehensive analysis of sickness and disability in common health problems, e.g. back pain and CFS.

Basically, it’s all about blaming the victim.

Dog whistles everywhere

Blaming-the-victim attitudes are contagious. They may be strong in Britain but in the popularist world they are spreading absolutely everywhere. Especially in disability medicine.

The European Union of Medicine in Assurance and Social Security EUMASS met in September, 2019. Its Vice President, Dr Gert Lindenger, gave a presentation entitled: How can social security/insurance better benefit from Cochrane Reviews?

One of Lindenger’s first slides reproduces the cartoon above. The joke sends a message. The audience smirks and smiles.

Nice to see Sir Mansel’s handiwork disseminating across Europe. The sophistication of the science may not bowl one over but, hey, nobody’s perfect. Look at this piece of epidemiological wisdom:

I bet you didn’t know that!? It’s got nothing to do with the government or Brexit or COVID-19. Dr Lindenger’s arrow is arriving near you.

More seriously, another of Dr Lindenger’s slides shows the sick leave figures from across Europe, 1987-2018.

The dog whistles are becoming a little shrill, perhaps, especially for the disability medics in Norway. But three cheers, for Sir Mansel and Sir Simon, the UK is up to speed and currently producing some of the lowest numbers of sick leavers right across Europe.

Another of Dr Lindenger’s slides asks: What is the essence of a work disability claim? he gives some straightforward answers:


• Very few medical conditions will with certainty lead to a completely reduced work ability.

• An assessment of work ability often involves interpretations which includes evaluations of where the limit is drawn for what strains and pressures that should normally be tolerated – what is reasonable for asking a claimant to contribute to his/hers own support?

Just an aside, from Unum’s perspective, a third related point, does the claimant perhaps have a work-related insurance policy that can’t pay out? If so, lovely jubbly!

Insurance Companies’ Involvement

Mansel Aylward, with most other members of the Wessely School, formed strong connections with the insurance industry and with UnumProvident and Swiss Re in particular. Here I discuss the profile of Unum.

In 2005 the California Department of Insurance investigations into Unum and found “widespread fraud”, prompting California Insurance Commissioner John Garamendi to describe Unum as an “outlaw company.”

In 2012 legal website LawyersandSettlements.com reported, “Unum continues to suffer from a global reputation that it denies, delays or discontinues benefits in an alleged attempt to wear down policyholders in their pursuit of legitimate benefits.”

The Unum/Provident Scandal

Unum provides the largest share of private sickness unemployment insurance in the US and UK. It isn’t all good news for Unum however. A Unum class action lawsuit in the US has been called “The Unum/Provident Scandal.

Unum (known then as Unum/Provident) was alleged to have denied or terminated thousands of legitimate disability claims starting in the 1990s and continuing until 2002.

The Unum class action lawsuit came about after an investigation by the US Department of Labor that put the long history of Unum claim denial under the microscope. The investigation also looked into Unum’s subsidiary companies, which at the time were Unum Life Insurance Company, Paul Revere Life Insurance Company, and Provident Life and Accident Insurance Company.

The Department of Labor found the company was acting “unfair and unjust” by deliberately resorting to fraudulent tactics of claim denial as a cost control measure. The claims involved employee group disability policies. In an investigation that involved insurance regulators from 48 states, lawsuits against Unum were granted class action status for violation of ERISA laws.

Under court order, Unum was directed to reopen more than 200,000 denied claims, and to reevaluate the claims based on their merit. Unum was charged with overhauling the methods by which they evaluate and process claims. Unum was also ordered to pay a fine of $15 million to several states.

Lesson Not Learned

After such legal actions and repercussions, Unum should have learned a lesson and learned to play by the rules. Not so.

According to the American Association for Justice in a document entitled: “The Ten Worst Insurance Companies in America“, where Unum is honoured with 2nd place, by 2007 Unum confessed that only 10 percent of the claims earmarked for reopening under the terms of the previous legal settlements had been reviewed.

New cases are ongoing

See this:

The Wessely School sure did choose some fine bedfellows.

Sir Mansel is now at a different Welsh university. Did something go wrong at Cardiff? Or is Swansea just nicer than Cardiff?

Probably.

Personal footnote

Oblivious to the context, I contributed by invitation a chapter to Halligan and Aylward’s book on The Power of Belief. My chapter about ‘subjective validation’ concerns a process that happens when one’s beliefs are confirmed by ambiguous or contrary evidence. It is especially prevalent in the field of the anomalous experiences e.g. the paranormal. I had already critiqued the biopsychosocial model in a co-authored textbook on Health Psychology, currently in its 6th edition. Awareness of the abuse of the BPSM in disability denial deepened this critique significantly.

Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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HYPOTHESIS AND THEORY ARTICLE

Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.62802

Dominic Stanculescu1Lars Larsson2 and Jonas Bergquist3,4*

  • 1Independent Researcher, Sint Martens Latem, Belgium
  • 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
  • 3Analytical Chemistry and Neurochemistry, Department of Chemistry – Biomedical Center, Uppsala University, Uppsala, Sweden
  • 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.

Introduction

Critical illness refers to the physiological response to virtually any severe injury or infection, such as sepsis, liver disease, HIV infection, head injury, pancreatitis, burns, cardiac surgery, etc. (1). Researchers make a distinction between the acute phase of critical illness—in the first hours or days following severe trauma or infection; and the chronic or prolonged phase—in the case of patients that survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (i.e., “chronic ICU patients”). Independent of the nature of the critical illness, the acute phase is associated with an excessive response of pro-inflammatory cytokines (2) and is characterized by a uniform dysregulation of the endocrine axes (3). In prolonged critical illness, this dysregulation is maintained even once the initial inflammatory surge has settled (4). Regardless of the initial injury or infection, patients that suffer from prolonged critical illness experience profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc. (156). Whereas, the acute phase is considered to be an adaptive response to the severe stress of injury or infection (shifting energy and resources to essential organs and repair), the physiological mechanisms in the prolonged phase are now increasingly considered to be maladaptive responses to the stress of severe injury or infection, hindering recovery (710). Some have also suggested that the non-recovery from endocrine disturbances could explain the development of “post-intensive care syndrome” (PICS) (11); i.e., “the cognitive, psychiatric and/or physical disability after treatment in ICUs” (1213).

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, multi-system disease of unclear etiology (1415). The most common peri-onset events reported by patients are infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%) (16). “Impaired function, post-exertional malaise (an exacerbation of some or all of an individual’s ME/CFS symptoms after physical or cognitive exertion, or orthostatic stress that leads to a reduction in functional ability), and unrefreshing sleep” are considered to be core symptoms (14). The severity of the symptoms varies: “very severely affected patients experience profound weakness, almost constant pain, severe limitations to physical and mental activity, sensory hypersensitivity (light, touch, sound, smell, and certain foods), and hypersensitivity to medications” (17). We have listed a few hall mark symptoms that are often found in critically ill patients in chronic intensive care (ICU) patients and ME/CFS patients (Table 1).TABLE 1

Table 1. Comparison of the typical clinical picture of ICU patients and patients with ME/CFS.

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some ICU patients also underlie ME/CFS. Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. These mechanisms characterize prolonged critical illness regardless of the nature of the initial severe injury or infection (3810); similarly, we propose that these mechanisms could underlie the perpetuation of illness in ME/CFS regardless of the nature of the peri-onset event (i.e., infection, stressful incident, exposure to environmental toxins, or other). We provide an overview of these mechanisms in ICU patients and discuss their relevance for understanding ME/CFS. We also bring findings from fibromyalgia into the discussion here because ME/CFS and fibromyalgia are often jointly considered in the literature (2021); fibromyalgia is similarly a syndrome that is medically unexplained, often comorbid with ME/CFS, and “shares the core symptoms of fatigue, sleep problems and cognitive difficulties” (22). Additional research projects are required to investigate the validity of this hypothesis building on the findings from critical illness and ME/CFS summarized here.

This hypothesis may be particularly relevant in light of the current COVID-19 pandemic. Many COVID-19 patients continue to experience a variety of debilitating symptoms despite successfully defeating the virus—termed “post COVID-19 syndrome” or “long COVID-19”—that resemble ME/CFS (2326).

Suppression of Pulsatile Pituitary Secretions

Endocrine patterns observed during the initial acute phase of critical illness (in the first few hours or days) differ markedly from those observed during prolonged critical illness (after a few days) (2728). Indeed, the acute phase is characterized by increased release of pituitary hormones; the prolonged phase is characterized by suppression of the release of pituitary hormones. Simultaneously, hormone half-life and hormone up-take by the peripheral tissues differ markedly between these two phases (429). This biphasic pattern of the endocrine system during critical illness, however, is not readily observable in single or average measurements of circulating tropic and non-tropic hormone concentrations—which are a function of both hormone release and elimination from the blood stream. This pattern was thus only discovered in the early 1990s with measurements of the frequency and amplitude of pituitary secretions (i.e., pulsatility) performed as often as every 10 min over 24 h on ICU patients (29). The pulsatility of tropic hormone secretion is part of the signaling to the peripheral glands and thus considered a determining factor of hormone function (i.e., impact on target glands or tissues), in addition to overall volume of hormone release (3031). The finding that pulsatile pituitary secretions are suppressed during prolonged critical illness was critical in understanding the physiology of the syndrome and the curious failure of patients to recover (32). We describe the biphasic endocrine patterns during acute and prolonged critical illness for each of the main endocrine axes in further detail below, as well as the implications for the autonomic nervous system, metabolism and the immune system. We also provide evidence suggesting that the endocrine patterns observed in prolonged critical illness also underlie ME/CFS.

The Adreno-Cortical Axis (HPA Axis)

The adreno-cortical axis—also called hypothalamic-pituitary-adrenal (HPA) axis—is the body’s primary stress management system. The HPA axis responds to physical and mental challenges in part by controlling the body’s glucocorticoids levels, notably cortisol (33). Cortisol in turn modulates inflammation response, cardiovascular function and glucose metabolism (34). An inability to deal with stress, proneness to exaggerated immune responses and weight loss are associated with hypocortolism or poor HPA axis function (3538). The HPA axis also regulates mineralocorticoids that, in turn, regulate water and electrolyte balance (i.e., blood pressure). Low blood pressure and dizziness upon standing up are associated with a compromised HPA axis (35). Finally, the HPA axis (in addition to the gonadotropic axis not covered here) also contributes to the production of androgens, notably DHEA and testosterone, which are steroids that impact muscle mass, fat storage, pain, brain function and many other physiological traits. Low androgens are associated with muscle fatigue, joint pain, and noise intolerance (3942).

In normal conditions, the adrenal gland secretes cortisol during the day in pulses, with the highest amounts in the early morning hours and lower amounts at night. The hypothalamus signals to the pituitary with corticotrophin-releasing hormone (CRH), and to a lesser extent, arginine vasopressin (AVP), to produce adrenocorticotropic hormone (ACTH). This is in turn signals the adrenals to release cortisol and other hormones. Most cortisol circulating in the blood is bound to carrier molecules (2943). Production of cortisol is regulated by an inhibitory feedback loop. When free circulating cortisol attaches to glucocorticoid receptors on the hypothalamus and pituitary, these glands reduce production of CRH and AVP, and ACTH, respectively. The number and affinity of glucocorticoid receptors is thus considered one of the most important determining factors in the regulation of the HPA axis (43)

In Critical Illness

During the acute phase of critical illness, plasma cortisol concentrations rise rapidly. Increased cortisol availability is considered a vital response that allows for fluid retention, increased cardiac output and blood pressure, and induces an appropriate immune response while protecting against excessive inflammation (294445). Until recently believed to be the result of increased cortisol production by the adrenals, it is now known that high cortisol availability during this phase of critical illness is in fact largely driven by two peripheral mechanisms: a decrease in the abundance and affinity of the cortisol carrier molecules in circulation, and a slowing of cortisol breakdown in the liver and kidney (2934444647). Via inhibitory feedback loops, these higher cortisol concentrations suppress the HPA axis at the central level: the secretions of CRH and AVP by the hypothalamus and of ACTH by the pituitary fall, leading to an eventual drop in plasma cortisol levels (48).

Whereas, in critically ill patients that begin to recover, the HPA axis essentially normalizes within 28 days of illness, in cases of prolonged critical illness ACTH levels (surprisingly) continue to be depressed despite dropping cortisol levels (4950). Why and how this central suppression of ACTH is maintained is not clear and continues to be debated. Pro-inflammatory cytokines and O&NS likely play a leading role. Cytokines can mediate tissue-specific changes in the abundance and affinity of glucocorticoid receptors—which are major factors determining the activity of the HPA axis (244). Specifically, the cytokine IL-1β is known to modulate CRH release by the hypothalamus; TNF-α is known to impair ACTH release by the pituitary; and TNF-α is also known to impair cortisol production by the adrenal glands (2).

Without sufficient pulsatile stimulation by the tropic hormone ACTH, adrenal glands begin to atrophy and lose zonational structure. This is evidenced in the post-mortem dissection of patients that had been critically ill for a few weeks, but not in the patients that quickly died from their illness or trauma (3451). The weakening of adrenal glands not only compromises patients’ ability to cope with external stressors but also permits excessive inflammatory responses. In sum, the initial beneficial increase in cortisol availability induced by peripheral mechanisms during the acute phase of critical illness leads to a suppression of the HPA axis at the central-level from which a subset of patients appears unable to escape (Figure 1).FIGURE 1

Figure 1. The adreno-cortical axis (HPA axis) during normal conditions and prolonged critical illness.

In ME/CFS

Dysfunction of the HPA axis has been documented extensively in ME/CFS patients since the early 1980s (5263). Researchers have observed decreased baseline cortisol levels, blunted HPA axis responses to physical and psychological stressors, reduced HPA axis responsivity to provocation tests (such as CRH and ACTH administration), and a heightened inhibitory feedback loop (consistent with a higher abundance and affinity of glucocorticoid receptors at the level of the pituitary and hypothalamus). Strikingly, the magnitude of HPA axis dysfunction becomes more pronounced with illness duration and is associated with symptom severity (4364). Very few have studied pulsatility of ACTH release: one study of 36 study-pairs found no statistically significant differences in ACTH pulsatility between ME/CFS and matched controls (65), while another found a differential pattern of ACTH release over 24-h periods (66). Variations in the study-participants’ severity of illness—and methods used to control for these—may explain these apparently contradictory findings. Several studies have found the morning peak of ACTH is missing or weak in ME/CFS patients (43). A recent study assessing secretory events of cortisol found that CFS/ME patients have the same number of secretory events but secrete lower quantities in early morning hours (67). Significantly, a group of ME/CFS patients were found to have 50% smaller adrenals than controls (68), resembling adrenal atrophy in prolonged critical illness.

ME/CFS researchers have also proposed models to explain the persistence of a suppressed HPA axis (336970). Essentially, a short stress (i.e., a burst of cortisol) will produce a small perturbation in the glucocorticoid receptor concentration on the central glands that quickly returns to normal levels. However, long, repeated stress—from which the system doesn’t have time to recover—leads to a persistent high glucocorticoid receptor concentration, forcing the HPA axis to an alternate steady state. More recent models of the HPA axis have also included non-genomic feedback-controls (71), the endogenous effects of circadian rhythm (72), and interactions with the gonadotropic axis and the immune system (7374) to explain how HPA axis suppression is maintained even after the initial stress is gone.

HPA axis dysfunction is also present in the majority of fibromyalgia patients (7577). Various mechanisms have been suggested, including depressed secretion of CRH by the hypothalamus, a deficiency of CRH receptors on the pituitary, and adrenal atrophy due to chronic under-stimulation by reduced ACTH levels (78).

Moreover, the dysfunction of the HPA axis in ME/CFS and fibromyalgia has also been associated with pro-inflammatory cytokines and O&NS (43557980). A recent paper considering the bidirectional relationship between the function of the HPA axis and inflammation finds that immune-inflammatory and O&NS pathways induce HPA axis dysfunction in ME/CFS (81); the direction of causality is analogous to inflammatory pathways inducing endocrine dysfunctions in critical illness. Others have similarly theorized that local inflammation in the hypothalamus leads to a disturbed HPA axis in ME/CFS (82).

In sum, the HPA axis dysfunctions in ME/CFS are not unlike the dysfunctions in prolonged critical illness. However, to our knowledge a comprehensive study of the pituitary pulsatile secretions of ACTH in ME/CFS patients—which proved revelatory in understanding prolonged critical illness—does not yet exist. The relationship between the pituitary’s pulsatile ACTH secretions, severity of illness, the integrity and function of adrenal glands and resulting physiological alterations in ME/CFS thus remains largely unexplored.

The Somatotropic Axis (HPS Axis)

The somatotropic axis—also called hypothalamic-pituitary-somatotropic (HPS) axis—plays important roles in growth and development of children, but also contributes to a variety of physiological pathways in adults, including balancing catabolic (i.e., the break-down of molecules and tissues) and anabolic activities (i.e., the building of molecules and tissue) (4). An HPS axis dysfunction is known to cause loss of muscle and bone mass, induces weakness (29), and impacts gut mucosa integrity as well as glucose and fat metabolism (83). Low energy, exhaustion, mental fatigue, weak muscle strength as well as poor recovery after physical activity are associated with an inhibited HPS axis function (428485).

Uniquely, in the case of the HPS axis, the hypothalamus sends both stimulating (+) and inhibiting (-) signals to the pituitary for the production of growth hormone (GH): these are, respectively, the GH-releasing hormone (GHRH) and the GH-inhibiting hormone (GHIH, also called somatostatin) (4). In addition, ghrelin, mostly produced by the gut, also stimulates GH production by the pituitary. In normal conditions, GH is released by the pituitary in a pulsatile fashion under the control of these three signals, with peaks of GH levels alternating with virtually undetectable valleys in 3- to 5-h intervals over the course of the day (29). GH in turn has direct effects on some tissues and also stimulates the production of insulin-like growth hormone-1 (IGF-1), mostly by the liver. Nearly all of the IGF-1 hormones in the plasma are bound to IGF-binding proteins (IGFBP). IGF-1 and GH exert inhibitory feedback on the hypothalamus and the pituitary to maintain homeostasis. The half-life of GH is only 10 to 20 min, whereas the half-life of IGF-1 is more than 12 h. Thus, IGF-1 plasma concentrations are regularly used as proxies for GH secretion in clinical settings. This, however, overlooks the function of the pulsatile secretion of GH on the balance of anabolic and catabolic activities in the body (4).

In Critical Illness

In the acute phase of critical illness, the pituitary produces more GH: higher peaks, lower valleys and increased pulse frequencies (86). The rapid onset of two main peripheral mechanisms explain this finding: First, under the influence of cytokines, the liver expresses fewer GH receptors (i.e., becomes resistant to GH) and thus produces less IGF-1. Second, alterations in IGF binding proteins results in IGF-1 being cleared out faster from the system (i.e., IGF-1 has a shorter half-life) (87). The lower IGF-1 concentrations resulting from these two peripheral mechanisms will—via the feedback loop inherent to the axis—spur more GH production (29). The resulting increase in catabolic activity during the acute phase of critical illness serves to mobilize amino acids derived from the breakdown of peripheral tissues, such as skeletal muscle and bone, for use by the central organs (4).

However, if a critically ill patient fails to recover within a few days, GH secretion becomes erratic and almost non-pulsatile. Experiments have demonstrated that this is largely due to a lack of stimulation of the hypothalamus and pituitary by the hormone ghrelin. There is also evidence for changes in the relative amounts of GHIH and GHRH signals from the hypothalamus (4). As for the peripheral hormone, IGF-1, its levels are low or normal in prolonged critical illness. The liver’s resistance to GH (which previously suppressed IGF-1 production during the acute phase of critical illness) does not persist during prolonged critical illness (2987). However, without a concomitant pulsatile release of GH, the anabolic function of IGF-1 becomes inhibited (4).

In sum, although the increase in catabolic activity during the acute phase of critical illness may initially be beneficial because it serves to mobilize amino acids, the perpetuation of the imbalance in catabolic vs. anabolic activity (due in part to the loss of the pulsatile function of GH) during prolonged critical illness may be considered maladaptive (Figure 2). The imbalance in catabolic relative to anabolic activity in prolonged critical illness leads to protein break-down in skeletal muscle, liver, kidney and heart, reducing their cell mass and leading to impaired function (7). These processes are ultimately reflected in muscle and bone wasting typically present in prolonged critical illness (8889).FIGURE 2

Figure 2. The somatotropic axis (HPS axis) during normal conditions and prolonged critical illness.

In ME/CFS

GH regulation in ME/CFS has been studied since the 1990s. The findings are mixed, but almost none addresses the question of the pulsatility of GH release. Some described low nocturnal GH secretion (9091), while others have found normal levels of 24-h urinary GH excretion (92). Some have found reduced response to induced hypoglycemia (9091), while others describe normal GH responses to stimulation (93). One study describes unaffected diurnal patterns of GH release in ME/CFS, but it focused on assessing basal levels rather than the nature of secretory patterns (i.e., pulsatile vs. erratic) and may not have accounted for variations in the severity of illness of patients (66). In terms of IGF-1, there are no consistent differences between ME/CFS patients and controls (9394), which is consistent with findings from prolonged critical illness.

Studies in fibromyalgia show relative GH deficiency (76789599) and low or low-normal IGF-1 levels (9596100). Interestingly, some studies showed that fibromyalgia patients “failed to exhibit a GH response to exercise” (97101), consistent with a loss in pulsatility of GH release.

In sum, endocrine observations in ME/CFS are not unlike HPS axis dysfunctions found in prolonged critical illness. To our knowledge the pituitary pulsatile secretions of GH in ME/CFS patients has not been comprehensively studied. The relationship between the pituitary’s pulsatile GH secretions, severity of illness and the balance between catabolic and anabolic activities in ME/CFS thus remains largely undiscovered.

The Thyrotropic Axis (HPT Axis)

The thyrotropic axis—also called hypothalamic-pituitary-thyroid (HPT) axis—regulates the basal rate of our metabolism. Dysfunctions of the HPT axis are associated with tiredness, stiffness, constipation, dry skin and weight gain, among a myriad of other hypothyroid-like symptoms (3542).

In normal conditions, an inhibitory feedback loop works to maintain stable circulating thyroid hormone concentrations according to a daily rhythm (102). When unbound circulating thyroid hormone concentrations dip below a certain threshold, the hypothalamus produces thyrotropin-releasing hormones (TRH) in order to signal the pituitary to produce thyroid stimulating hormone (TSH), which in turn signals the thyroid gland to produce more thyroid hormones.

In Critical Illness

Dysfunctions of the HPT axis during critical illness have been studied extensively. Starting in the early 1970s, clinicians working in ICUs observed that patients with a wide range of critical conditions had low plasma concentrations of the active form of thyroid hormones (T3) relative to plasma concentrations of inactivated thyroid hormones reverse T3 (rT3) (103105). They gave this condition the name “non-thyroidal illness syndrome” (NTIS), also called “euthyroid sick syndrome” or “low T3 syndrome.” While NTIS was initially considered to be beneficial in critical illness—i.e., a state of “protective” down-regulation of metabolism during times of duress (106) —it is increasingly seen as maladaptive and hampering the recovery of patients in the case of prolonged critical illness (91029103104107108).

During acute and early stages of critical illness, peripheral mechanisms involving cytokines (notably IL-1β, IL-6, TNF-α) lead to the quick depression of thyroid hormone activity (104105109111) to help conserve energy resources (48104). The mechanisms include the alterations in the amount and affinity of thyroid hormone binding globulines in the blood (112114); modifications in the expression of the transporters that carry the thyroid hormone into the cells (115116); the down- and up-regulation of deiodinase enzymes that convert the thyroid hormone into active and inactive forms, respectively (113117); and the variation in the quantity and isoforms of cellular thyroid hormone receptors present (notably in the liver, adipose tissue and muscle) (118120). An alteration in any of these steps—which determine thyroid hormone function—can lead to large time- and tissue-specific adjustments in cellular metabolism (121122)—even without, or with only minor, changes in the blood concentrations of thyroid hormones (121123124).

During prolonged critical illness these peripheral mechanisms are supplemented by central mechanisms that also depress thyroid hormone function (125126). Cytokines (notably IL-12 and IL-18), in association with other signaling factors (including leptin, glucocorticoids, etc.), are believed to up-regulate the deiodinase enzymes D1 and D2 in the hypothalamus resulting in higher local levels of T3 that inhibit TRH release irrespective of circulating thyroid hormone concentrations (10127128). Moreover, cytokines (notably IL-1b and TNF-α) also suppress the release of TSH by the pituitary (129130). Finally, by reducing iodine uptake and thyroid hormone excretion, cytokines (notably IL-1) also impact the activity of the thyroid gland itself (103113). Together, these mechanisms can alter the inhibitory feedback mechanisms of the HPT axis (i.e., its “set-point”) during prolonged critical illness. Single measurements of circulating TSH, however, are ineffective in revealing such alterations in the set-point of the HPT axis.

In sum, an initial beneficial alteration of thyroid hormone activity in the periphery during acute critical illness is followed by a cytokine-mediated central suppression of the HPT axis resulting in a virtual complete loss of pulsatile TSH secretion (29). Peripheral mechanisms (notably variations in the conversion and transport of thyroid hormones) may further modulate thyroid hormone function in time- and tissue-specific ways resulting in complex physiological alterations in these patients (Figure 3) —not readily observable in blood concentrations of thyroid hormones. How these alterations of the HPT axis persist as well as their broader implications on metabolism and the immune system are further described below (see section A “Vicious Circle” Perpetuating Illness).FIGURE 3

Figure 3. The thyrotropic axis (HPT axis) during normal conditions and prolonged critical illness.

In ME/CFS

Dysfunctions of the HPT axis have long been suspected to play a role in ME/CFS (77131134) and fibromyalgia (135140). A recent study showed that ME/CFS patients had similar TSH levels as controls, but lower Free T3, Total T4, and Total T3, which the authors suggest resembles NTIS (141)—the typical feature of critically ill patients in ICUs described above.

In sum, alterations of the HPT axis in ME/CFS resemble dysfunctions found in prolonged critical illness. However, there does not to our knowledge exist a thorough study of the pulsatility of pituitary TSH secretion events in ME/CFS patients, nor a study of the tissue-specific alterations in thyroid hormone function—which proved revelatory in understanding prolonged critical illness. The relationship between the TSH axis dysfunctions, severity of illness, hypometabolic state and organ/tissue specific symptoms in ME/CFS thus remains largely unexplored.

Intermediate Conclusions

The endocrine axes control many of the most fundamental physiological processes; their suppression is associated with a myriad of symptoms (see Table 2). Essentially, the suppression of pulsatile pituitary secretions of ACTH, GH, and TSH are central to prolonged critical illness. Inflammatory pathways play a role in inducing and maintaining this suppression irrespective of the nature of the original illness or trauma (see Table 3). The resulting endocrine patterns may be considered maladaptive and have wide ranging implications, including dysfunction of the balance between anabolic and catabolic processes, metabolism, and the regulation of the immune system. The physiological parallels between ME/CFS and prolonged critical illness would suggest that the suppression of pulsatile pituitary secretions of these tropic hormones might also underlie ME/CFS, and that the severity of ME/CFS might be a function of the strength of the mechanism; this however remains largely unstudied. In the next section we provide an overview of a model from critical illness that explains the perpetuation of these endocrine dysfunctions and we describe the relevance of the model for understanding ME/CFS.TABLE 2

Table 2. Summary of endocrine axes and function of the main hormones in adults.TABLE 3

Table 3. Summary of endocrine dysfunctions and mechanisms in critical illness and ME/CFS.

A “Vicious Circle” Perpetuating Illness

Based on nearly five decades of research, critical illness researchers have proposed a model that describes how NTIS is maintained by reciprocal relationships between inflammation (notably pro-inflammatory cytokines), O&NS and reduced thyroid hormone function, forming a “vicious circle” (910) (Figure 4). This model can help to explain the perplexing failure to recover of some critically ill patients in ICUs that survive their initial severe illness or injury. We describe the main elements of this model in a simplified manner below, as well as the implications for metabolism and the immune system. We also provide evidence suggesting that the “vicious circle” observed in prolonged critical illness also underlies ME/CFS.FIGURE 4

Figure 4. Simplified model to explain the perpetuation of prolonged critical illness: a “vicious circle”.

In Prolonged Critical Illness

The key elements of the suggested “vicious circle” in prolonged critical illness include the following mechanisms:

(a) Cytokines depress thyroid hormone function: As described above [see section The thyrotropic axis (HPT Axis) In Critical Illness], in acute and early stages of critical illness, various peripheral mechanisms involving cytokines lead to the quick depression of thyroid hormone activity in tissue-specific ways. In prolonged critical illness, cytokines in association with other signaling factors targeting the hypothalamus, as well as the pituitary and the thyroid glands, also inhibit thyroid hormone production. The relative sequence and importance of these various mechanisms in depressing the HPT axis and thyroid hormone function in different tissues and phases of critical illness are the subject of most NTIS publications (10104105). Notwithstanding the effect of other mechanisms, alterations in the activity of the deiodinase enzymes lead to a decrease in T3 and an increase in rT3 and thus a reduction in thyroid hormone function in peripheral tissues during prolonged critical illness [based on biopsies on ICU patients who died (142) and studies on mice (143144)]. Circulating thyroid hormone concentrations, however, only reveal the “tip of the iceberg” of the alterations occurring at the tissue level (141145), which thus are often missed altogether in clinical settings (146).

(b) Low thyroid hormone function contributes to oxidative and nitrosative stress: The relationship between thyroid hormone function and O&NS is complex, and both hyperthyroidism and hypothyroidism have been associated with oxidative stress (147). Nonetheless, it seems clear that depressed thyroid hormone function hinders tissue cells from maintaining a healthy O&NS balance. Mechanisms include alterations to the lipid concentration of the cell membranes that maintain the cell’s O&NS balance (148), and reduced function of two proteins (Uncoupling Proteins-2 and -3) with anti-oxidant properties (149). Moreover, in low thyroid hormone function conditions, mitochondria damaged by O&NS are not cleared out of cells (9). In turn, it appears that oxidative stress depletes the glutathione required by the abovementioned deiodinase enzymes for the conversion of T4 into T3 (104). Similarly, competition for, and the resulting depletion of the trace mineral selenium—a component of both the deiodinase and the anti-oxidant enzymes (150) —may amplify the self-perpetuating link between increased oxidative stress and low thyroid hormone function.

(c) Oxidative and nitrosative stress stimulate the production of pro-inflammatory cytokines: The final mechanism which completes the “vicious circle” in prolonged critical illness is the link between O&NS and inflammation. O&NS stimulates the production of pro-inflammatory cytokines, notably leptin, resistin, TNF-α and IL-6 (151). In turn, pro-inflammatory cytokines (notably IL-6) further increase O&NS by triggering the production of superoxide radicals (104152). There is thus a tendency for O&NS and pro-inflammatory cytokines to perpetuate each other as well.

In sum, according to a model proposed by critical illness researchers, a “vicious circle” involving O&NS, pro-inflammatory cytokines, and low thyroid hormone function—as well as reciprocal relationships across these elements—can perpetuate a hypometabolic and inflammatory state, and thus help to explain why some critically ill patients fail to recover.

In ME/CFS

Similar patterns of O&NS, cytokines, and low thyroid hormone function have recently been documented in ME/CFS patients providing the elements for a similar “vicious circle.” We briefly summarize the findings from ME/CFS research relevant to each of these elements.

Reduced thyroid hormone function: An immune-mediated loss of thyroid hormone function in ME/CFS has long been suspected (132). As mentioned above [see section: The thyrotropic axis (HPT Axis) In ME/CFS], a recent study confirmed that CFS patients have lower circulating levels of Free T3, Total T4, and Total T3 than controls (141). Moreover, this study found a significantly higher ratio of rT3 to T3 hormones. These findings imply a depressed thyroid hormone function resembling NTIS. Given the possible tissue-specific alterations in thyroid hormone activity resulting from peripheral mechanisms, the authors suggest these circulating levels only reflect the “tip of the iceberg” of genuine T3 deficits in target tissues.

Oxidative & nitrosative stress: Numerous studies have found increased O&NS in ME/CFS and identified this as a factor in the observed metabolic dysfunction (153154). Indeed, Pall proposed a model that describes a “vicious circle” involving oxidative stress and cytokines in ME/CFS a decade ago (cf. the “NO/ONOO-Cycle”) (155). Researchers also suggest that high lactate and low glutathione levels found in the brains of ME/CFS patients likely derive from similar mechanisms involving oxidative stress (156). A recent study described the relationship between O&NS and immune-inflammatory pathways in ME/CFS (80).

Pro-inflammatory cytokines: Neuro-inflammation is central to ME/CFS, and many researchers have tried to develop diagnostic biomarkers for ME/CFS based on cytokine profiles of patients (157158). Montoya et al. found that some 17 cytokines were positively correlated with the severity of ME/CFS, of which 13 are pro-inflammatory. Similarly, circulatory levels of pro-inflammatory cytokines are altered in fibromyalgia patients (159). However, others have argued that given the innumerable sources of potential variance in the measurement of cytokines, it is “unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered” for ME/CFS (160). It may therefore be ineffectual to compare the cytokine profiles of ME/CFS and prolonged critical illness patients.

In sum, given the presence of reduced thyroid hormone function, O&NS and pro-inflammatory cytokines in ME/CFS, the “vicious circle” model proposed by critical illness researchers to explain prolonged critical illness may also help to understand why ME/CFS patients fail to recover.

Implications of the “Vicious Circle” and Its Elements

Reduced thyroid hormone function, increased O&NS and pro-inflammatory cytokines discovered in prolonged critical illness as well as in ME/CFS have important implications notably on metabolism, organ function, immune responses and the endocrine system. These are further described below:

Reduced thyroid hormone function: The prolonged down-regulation of thyroid hormone activity certainly has implications for the immune system. Authors describe the profound effects of circulating thyroid hormone levels on the activity of monocytes, lymphocytes macrophages, neutrophils, dendritic cells and natural killer cells; as well as cytokines (161170). Notably, depressed thyroid levels appear to depress the activity of natural killer cells (171)—a signature finding in ME/CFS (172). Such immune dysfunctions might explain other pathologies, such as viral reactivation observed in ICU patients (173175) and suspected in ME/CFS patients (176177). Experimenting on rats, researchers have shown that depressed thyroid hormone levels occur in a specific sequence, manifesting (from first to last) in the liver, kidney, brain, heart and adipose tissues (145). An implication of a tissue-specific down-regulation of thyroid hormone activity is differential impact on organ function. Some ME/CFS practitioners have argued that tissue-specific modulation of T3 can help explain the disparate and evolving symptoms in ME/CFS and fibromyalgia (133134138140). In aggregate, depressed thyroid hormone function would engender a general hypometabolic state. Finally, thyroid hormone function also impacts other endocrine axes as well (178179)—notably the HPA axis—setting the stage for further complex interactions between the various endocrine axes and the immune system.

Oxidative & nitrosative stress: The implications of chronic oxidative stress in the body are widely documented. In addition to inducing inflammation, oxidative stress causes cell damage and disrupts normal cellular transcription and signaling mechanisms (9). O&NS has been shown to cause mitochondrial damage during critical illness (180) and ME/CFS (153).

Pro-inflammatory cytokines: Researchers are finding that the more than 100 different cytokines play a part in determining the function of hormones through both central and peripheral mechanisms (32). As described in the previous section, cytokines are likely culprits in the central (i.e., hypothalamic and pituitary) suppression of the HPA, HPS and HPT axes in prolonged critical illness (29). Pro-inflammatory cytokines and inflammation also hinder normal mitochondrial function during critical illness (181). The alterations in cytokines found in critical illness likely have many further implications that have yet to be fully understood (182) which is also the case for ME/CFS (183).

Intermediate Conclusions

In sum, critical illness researchers have proposed that the self-perpetuating relationships between inflammation (notably pro-inflammatory cytokines), O&NS and low thyroid hormone function explains the maintenance of illness in some ICU patients following severe injury or infection. Given that the same elements of such a “vicious circle” have also been documented in ME/CFS, we suggest that the model can also explain the failure of ME/CFS patients to recover. Moreover, these elements have been shown to have profound implications on metabolism, as well as on the function of the immune and endocrine systems—which in in turn could explain the myriad of symptoms in prolonged critical illness and ME/CFS.

Relationship to Other Hypotheses of ME/CFS Pathogenesis

Our hypothesis that maladaptive mechanisms which prevent recovery in prolonged critical illness also underlie ME/CFS complements several other hypotheses of ME/CFS pathogenesis. In this section we provide an initial and non-exhaustive discussion of some of these complementarities.

Allostatic overload: Some researchers consider ME/CFS to be a maladaptive response to physical, infectious, and/or emotional stressors. They describe an “allostatic overload” (i.e., the cumulative effect of stressful situations exceeding a person’s ability to cope) or a “‘crash’ in the stress system” (184185). Our hypothesis fits into this theoretical framework and offers an explanation for the possible underlying physiological mechanisms by drawing on the research from critical care medicine.

Hypothalamic endocrine suppression: Researchers have suggested that hypothalamic endocrine suppression could explain ME/CFS (132186) and fibromyalgia (187189). Our thesis upholds this hypothesis and seeks to strengthen it by suggesting that the controversy around the existence of central endocrine suppression in ME/CFS may be resolved by studying the pulsatile secretions of the pituitary—rather than single or average measurements of circulating tropic and non-tropic hormone concentrations, which can fail to discern the dysfunctions of the endocrine axes.

Anomalies in thyroid hormone function: Numerous clinical practitioners and researchers believe that anomalies in thyroid hormone function—including changes in the conversion of thyroid hormones, a resistance of thyroid hormone receptors at cellular level, etc. —contribute to ME/CFS and fibromyalgia (133141). Indeed, practitioners have written about their successes in treating ME/CFS patients with thyroid hormone supplements (4277188190194); and patients have published books on their experiences (195197). Our hypothesis complements this reasoning: we propose that both the central and peripheral mechanisms altering thyroid hormone function during critical illness (c.f. NTIS, euthyroid sick syndrome or “low T3 syndrome”) also occur in ME/CFS. Moreover, by applying a model from critical illness, we suggest that low thyroid hormone function is one element of a “vicious circle” perpetuating illness in ME/CFS.

Viral Reactivation: It has long been suggested that viral reactivation plays a role in ME/CFS, particularly reactivation of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) (176177). Similarly, high incidences of viral reactivation have also been observed in ICU patients, notably in patients with sepsis and prolonged critical illness. ICU researchers propose that this viral reactivation is a result of immune suppression occurring during critical illness (173175). Thus, critical illness research would suggest that viral reactivation is a secondary pathology in ME/CFS—except in cases in which the viral infection was the onset event.

Viral infection: Viral infection is recognized to be a leading onset event of ME/CFS (16198201). This is particularly concerning in the context of the COVID-19 pandemic. Many COVID-19 patients continue to experience a variety of debilitating symptoms after defeating the virus that resemble ME/CFS. Building on our hypothesis, we would suggest that post COVID-19 syndrome is evidence of a maladaptive response to the stress of infection akin to that experienced in prolonged critical illness and ME/CFS.

Chronic inflammation: Researchers have found that chronic inflammation—auto-immune, allergic or bacterial/viral—underlies ME/CFS (194202203). Others also ascribe the perpetuation of ME/CFS to the relationship between inflammation and O&NS (80155). Our hypothesis is largely complementary to these findings and associated theories. Indeed, following a cytokine surge during the acute phase of critical illness, inflammation is believed to persist in the case of prolonged critical illness (4). Moreover, pro-inflammatory cytokines and O&NS are elements in the “vicious circle” model of prolonged critical illness, which we propose also serves to understand the perpetuation of illness in ME/CFS patients.

Neuroinflammation of the brain: ME/CFS is associated with inflammation of the brain (hence the name myalgic encephalomyelitis) (204205). Some have specifically proposed that inflammation of the hypothalamus underlies ME/CFS (8182). Similarly, alterations of the endocrine axes through mechanisms mediated by pro-inflammatory cytokines which impact the hypothalamus and pituitary are central to prolonged critical illness (see section Suppression of Pulsatile Pituitary Secretions).

Energy metabolic defect: Researchers have found impairment in energy production (205206), reduced mitochondrial activity (207209) and irregularities in the metabolites of ME/CFS patients (210211) —suggesting that they experience a hypometabolic or “dauer” state (212). Our hypothesis is compatible with analyses that emphasize metabolic defects in ME/CFS. Indeed, the suppression of pituitary secretions, depressed thyroid hormone function, O&NS and immune system dysfunction—hallmarks of prolonged critical illness—have severe impacts on metabolism, including on glucose utilization and mitochondrial activity (see section A “Vicious Circle” Perpetuating Illness). Certainly, prolonged critical illness resembles a hypometabolic “dauer” state as well.

Genetic predisposition: Research also suggests there may a genetic element in the pathogenesis of ME/CFS (213216). Our hypothesis is compatible with a possible genetic predisposition for ME/CFS. Indeed, it is not known why some critically ill patients succumb to prolonged critical illness while others begin recovery (217218); genetics may play a role. The findings from the field of ME/CFS in the area of genetics might inform the field of critical illness in this regard.

In sum, our hypothesis is largely complementary to hypotheses that emphasize metabolic, hormonal and/or immune dysfunctions in the pathogenesis of ME/CFS. Our hypothesis—drawing from research on critical illness—integrates these dysfunctions into a single framework and provides arguments for the direction of causality between them.

Conclusion

Decades of research in the field of critical medicine have demonstrated that in response to the stress of severe infection or injury, endocrine axes experience profound alterations. An assessment of the pituitary’s pulsatile secretions reveals that in the subset of patients which survive their severe infection or injury but do not begin recovery (i.e., prolonged critically ill patients), the suppression of endocrine axes is maintained irrespective of the initial severe infection or injury. Recent pathological models propose that mechanisms involving pro-inflammatory cytokines, O&NS and low thyroid hormone function explain the perpetuation of these endocrine dysfunctions (i.e., a “vicious circle”).

The symptoms, physiological abnormalities and endocrine patterns observed in severe ME/CFS are not unlike those of prolonged critical illness. Moreover, the same elements of a “vicious circle” also exist in ME/CFS. However, unlike in critical illness, the pituitary’s pulsatile secretion and its relationships to metabolic and immune functions remain largely unstudied in ME/CFS.

Without excluding possible predisposing genetic or environmental factors, we propose the hypothesis that the maladaptive mechanisms that prevent recovery of prolonged critically ill patients also underlie ME/CFS. The severity of ME/CFS illness may be a function of the strength of these mechanisms; very severe ME/CFS most resembles prolonged critical illness. We further argue that this hypothesis should be investigated through collaborative research projects building on the findings from critical illness and ME/CFS. If this hypothesis is validated, past trials to break the “vicious circle” that perpetuates critical illness, and the early successes to reactivate the pulsatile secretion of the pituitary in ICU patients, may provide avenues for a cure for ME/CFS—including cases onset by infections. Certainly, given the similarities described above, active collaboration between critical illness and ME/CFS researchers could lead to improved outcomes for both conditions.

Finally, we suggest that immediate collaborative efforts should be sought among the researcher community in order to conduct longitudinal studies with the aim of identifying similarities and differences across prolonged critical illness, post-ICU syndrome, ME/CFS, fibromyalgia and long-COVID in relation to the hormonal axes, O&NS and pro-inflammatory response with the objective of discovering diagnostic and therapeutic targets mitigating the functional disability that these conditions induce.

Data Availability Statement

The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Author Contributions

DS wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Funding

Open Medicine Foundation and Swedish Research Council (2015-4870 (JB)) are acknowledged for support.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

Text throughout this hypothesis is reproduced from DS’s blogposts on Health Rising (219221) licensed Creative Common–Attribution CC BY.

Abbreviations

ACTH, Adrenocorticotropic hormone; ARV, Arginine vasopressin; CRH, Corticotrophin-releasing hormone; DHEA, Dehydroepiandrosterone; GH, Growth hormone; GHIH, Growth hormone inhibiting hormone; GHRH, Growth hormone releasing hormone; HPA, hypothalamus-pituitary-adrenal axis: “Adreno-cortical axis”; HPS, Hypothalamic-pituitary-somatotropic axis: “Somatropic axis”; HPT, Hypothalamic-pituitary-thyroid: “Thyrotropic axis”; ICU, Intensive Care Unit; IGF-1, Insulin like growth hormone-1; IGFBP, Insulin like growth hormone binding proteins; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NTIS, Non-thyroidal illness syndrome; O&NS, oxidative and nitrosative stress; PICS, Post-intensive care syndrome; POTS, Postural Orthostatic Tachycardia Syndrome; TRH, Thyrotropin-releasing hormone; TSH, Thyroid stimulating hormone.

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Keywords: myalgic encephalomyelitis, critical illness, non-thyroidal illness syndrome, low t-3 syndrome, pituitary, cytokines, oxidative and nitrosative stress, post-intensive care syndrome

Citation: Stanculescu D, Larsson L and Bergquist J (2021) Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front. Med. 8:628029. doi: 10.3389/fmed.2021.628029

Received: 10 November 2020; Accepted: 08 January 2021; Published: 28 January 2021.

Edited by:Nuno Sepulveda, Charité–Universitätsmedizin Berlin, Germany

Reviewed by:Jose Alegre-Martin, Vall d’Hebron University Hospital, Spain
Klaus Wirth, Sanofi, Germany
Jonathan Kerr, Norfolk and Norwich University Hospital, United Kingdom

Copyright © 2021 Stanculescu, Larsson and Bergquist. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jonas Bergquist, Jonas.Bergquist@kemi.uu.se

ME/CFS: evidence for an autoimmune disease

Featured

Autoimmunity Reviews

Volume 17, Issue 6, June 2018, Pages 601-609

Autoimmunity Reviews

ReviewMyalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease

FranziskaSotznya

JuliàBlancobc

EnricaCapellide

JesúsCastro-Marrerof

SophieSteinera

ModraMurovskag

CarmenScheibenbogena on behalf of the European Network on ME/CFS (EUROMENE)

Citehttps://doi.org/10.1016/j.autrev.2018.01.009Get rights and content

Under a Creative Commons license open access

Highlights

The pathogenesis of ME/CFS is multifactorial, and immunological and environmental factors play a role.•

Autoimmune mechanisms can be linked with ME/CFS at least in a subset of patients.•

Autoantibodies mostly against nuclear and neurotransmitter receptors are found in a subset of ME/CFS patients.•

Immunomodulatory therapeutic strategies targeting autoantibodies may be beneficial and should be pursued.

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levelsT- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.

Abbreviations

AdRadrenergic receptorBAFFB-lymphocyte activating factordUTPasedeoxyuridine 5′-triphosphate nucleotidohydrolaseEBVEpstein-Barr virusFMfibromyalgia5-HT5-hydroxytryptanimeHHVhuman herpes virusIFNγinterferon gammaKIRkiller cell immunoglobulin-like receptorM AChRmuscarinic acetylcholine receptorME/CFSMyalgic Encephalomyelitis/Chronic Fatigue SyndromeMSmultiple sclerosisNKnatural killer cellsPBMCperipheral blood mononuclear cellsPOTSpostural orthostatic tachycardia syndromepSSprimary Sjögren’s syndromeRArheumatoid arthritisSLEsystemic lupus erythematosusSNPsingle nucleotide polymorphismsTCAtricarboxylic acidTfhT follicular helper cellsThT helper cellsTNFαtumor necrosis factor alphaTregregulatory T cells

Keywords

Autoimmune Biomarker Myalgic Encephalomyelitis Chronic Fatigue Syndrome Autoantibodies

1. Introduction

With an estimated prevalence of 0.2–0.3%, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem disease with unknown etiology. Patients suffer from persistent exhaustion, cognitive impairmentautonomic dysfunction, chronic pain and flu-like symptoms, leading to a substantial reduction of life quality [1].

ME/CFS disease onset is often reported to be triggered by infections and the link between infections and autoimmune diseases is well established [2]. Although the exact pathogenesis is still unknown, the most plausible hypothesis is that dysregulation of immune system, autonomic nervous system and metabolic disturbances contribute to this complex syndrome, in which severe fatigue and cognitive impairment are a central feature (Fig. 1). Stressful life events are frequently associated with disease onset concomitantly with a history of frequent recurrent infections, immune deficiency and autoimmunity [1,3]. There are numerous studies showing immunological, genetic and metabolic alterations consistent with an autoimmune mechanism. Further, the identification of autoantibodies in ME/CFS patients and the clinical benefit associated with B cell depleting therapy provide strong evidence that, at least in a subset of ME/CFS patients, the disease has an autoimmune etiology.

Fig. 1

2. Evidence for autoimmunity in ME/CFS

2.1. Role of infection

Infection by various pathogens, including the Epstein-Barr virus (EBV), the human herpes virus (HHV)-6 and the human parvovirus B19, but also intracellular bacteria, are known as triggers of disease [1,[4][5][6]]. In a subset of patients, ME/CFS begins with infectious mononucleosis and evidence for a potential role of EBV in ME/CFS comes from many studies [4,[7][8][9]]. In 1984, DuBois et al. first described patients with mononucleosis syndrome suffering from long-lasting fatigue and serological evidence of EBV reactivation [4] followed by a number of studies describing ME/CFS patients with serological evidence of chronic active EBV infection [[7][8][9]]. Infectious mononucleosis is known as a risk factor for various autoimmune diseases [2,10]. Several studies show homologies of EBV sequences with human autoantigens such as myelin basic protein for multiple sclerosis (MS) [11]. In a study from our group enhanced IgG reactivity against an EBNA-6 repeat sequence was found in ME/CFS patients [9]. Homologous sequences of various human proteins with an EBNA-6 repeat sequence might be potential targets for antigenic mimicry.

Detection of anti-HHV-6 IgM antibodies and HHV-6 antigen in peripheral blood mononuclear cells (PBMC) and mucosa as evidence for HHV-6 reactivation is more frequent in patients with ME/CFS compared to healthy donors, showing that reactivation of persistent HHV-6 infection could be a trigger factor for ME/CFS [[12][13][14][15]]. In studies from our group evidence for an active HHV-6, HHV-7 or B19 infection was found in a subset of patients and was associated with subfebrility and lymphadenopathy [16]. Others, however, showed no difference between severity of symptoms and viral load of HHV-6 and HHV-7 in DNA from saliva and PBMCs among ME/CFS patients and controls [17]. It should be noted that HHV-6 and HHV-7 infect immune cells, preferentially CD4+ T cells, but also CD8+, monocytes/macrophages and natural killer (NK) cells involved in cellular, humoral and innate immune response [18,19]. Infection of immune cells by these viruses lead to changes in cell surface receptor expression, pro-inflammatory and anti-inflammatory cytokine and chemokine expression level modulating local inflammation and immune response. A role for HHV-6 has been proposed in several autoimmune diseases, including MS, autoimmune connective tissue diseases, and Hashimoto’s thyroiditis [20]. Molecular mimicry between myelin basic protein and an HHV-6 cell membrane protein is suggested to explain this link in MS [21]. Further, for ME/CFS and Gulf War Illness antibodies against the human dUTPase were reported by Halpin et al. [22]. These autoantibodies mainly occur together with antibodies against at least one of multiple HHV-encoded dUTPases suggesting an antigenic mimicry.

Parvovirus B19 infection has been shown to lead to development of ME/CFS. B19-triggered ME/CFS may be associated with a persistent viremia or may occur without viremia [23] and increased circulating TNF-α and IFN-γ were shown [24]. B19-associated ME/CFS was, in some cases, effectively treated with intravenous IgG [5,25,26]. Documented mechanisms in the pathogenesis of B19-associated autoimmunity include cross reaction of anti-B19 antibodies with human proteins, B19-induced apoptosis which results in presentation of self- antigens to T lymphocytes, and the phospholipase activity to the B19 unique VP1 protein region [23].

2.2. Immune cell alterations

Enhanced levels of immunoglobulins and alterations in B cells are frequently found in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) [[27][28][29][30]]. Further frequencies of CD21low B cells are frequently increased in these autoimmune diseases [27]. Consistently, alterations of B cell subsets are reported in ME/CFS. Elevated numbers of CD21+ as well as CD19+ and activated CD5+ B cells were described in ME/CFS patients [31,32]. Bradley et al. showed enhanced frequencies of naïve and transitional B cells and diminished plasma blasts [33]. Differently, Brenu et al. did not observe an altered frequency of plasma blasts, but an increase of memory B cells [34]. However, no major alteration of major B cell subpopulations was observed in other studies [3,35]. Mensah et al. reported an increase in CD24+ B cells, a fraction found to be elevated in autoimmune diseases [35]. Further elevated IgG levels in a subset of ME/CFS patients were shown in several studies [3,35,36]. Recently, a whole blood gene expression study discovered a downregulation of genes being involved in B cell differentiation and survival in ME/CFS [37].

T cell activation by infections could play an important role in the onset of autoimmune diseases [38]. In ME/CFS individuals, an increased frequency of activated T cells expressing the activation marker CD26 and HLA-DR has been shown, concomitant to lower levels of CD45RA+CD4+ T cells [31]. Similarly, ME/CFS was associated with higher frequencies of CD38 and HLA-DR co-expressing CD8+ T cells [39]. However, other authors found similar or lower expression of these markers in ME/CFS patients compared to healthy individuals [40,41]. Similarly, there is also evidence for a decreased cytotoxicity of CD 8+ T cells in a subset of ME/CFS patients [[42][43][44][45]]. Of particular interest in autoimmune diseases are T follicular helper cells (Tfh) that induce humoral responses at the germinal centers [46], the anti- inflammatory regulatory T cells (Treg) and the inflammatory T helper 17 (Th17) cells that modulate the activity of autoimmune responses [47]. The frequency of Treg has been addressed by several authors, most of them reporting a paradoxical higher frequency of this cell population in ME/CFS [40,42,48]. However, no studies on the potential role of Tfh and Th17 cells are available in ME/CFS yet.

In contrast to inconsistent B and T cell alterations reported in ME/CFS, diminished numbers of circulating NK cells and reduction of their cytotoxic activity were uniformly shown [31,40,49]. However, enhanced secretion of IFNγ and TNFα by the immunoregulatory CD56 bright NK cell subset was described in ME/CFS [49,50].

In summary, immune dysfunction in ME/CFS, as for other autoimmune disease, is a multifaceted hallmark that requires further studies using new technologies, standardized assays and well defined cohorts to clearly define common patterns.

2.3. Autoantibodies in ME/CFS

Several studies described autoantibodies in ME/CFS mostly against nuclear and membrane structures and neurotransmitter receptors (Table 1).

Table 1. Autoantibodies in ME/CFS.

AutoantigenCohorts of patients/control (n)Autoantibody positive
patients/control (%)
Refs.
Nuclear structures
ANA60/5168/15[51]
22523[53]
6057[54]
6068[55]
139/1497/5 (BioPlex ANA screen) 4/6 (IIF)[57]
Nuclear envelope60/5152/2[51]
60/3052/3[55]
Reticulated speckles60/3025/0[55]
68/48 kDa protein114/3713/0[52]
dsDNA8112[56]
Membrane structures
Phospholipids4238[58]
Cardiolipin2692 (IgM)[59]
4095 (IgM)[60]
814[56]
Phosphatidylserine815[56]
Gangliosides42/100 (FM)43[58]
Neurotransmitter receptors and neurotransmitter
M AChR5/11PET: binding to brain
M AChR in ME/CFS
[61]
M1 AChR60/3053/0[54]
M3/4 AChR and ®2-AdR268/108significantly elevated compared to
healthy controls
[53]
5-HT4262[58]
819[56]
Other autoantibodies
Cytoplasmic intermediate filaments60/3035/13[55]
dUTPase55/15115/5[22]
Neopitopes formed by oxidative or nitrosative damage14/11Significantly elevated compared to healthy controls (IgM titers)[66]
16/17[67]

Abbreviations: ANA: antinuclear antibodies; 5-HT: 5-hydroxytryptamine; IIF: indirect immunofluorescence; dUTPasedeoxyuridine 5′-triphosphate nucleotidohydrolase; FM: fibromyalgia.

2.3.1. Autoantibodies against nuclear and membrane structures

Antinuclear antibodies (ANA) were found in one study in 68 % of ME/CFS patients with the majority directed against the nuclear envelope [51]. Further studies showed ANA in 68%, 57%, 23% and 13% of ME/CFS patients [[52][53][54][55]]. Ortega-Hernandez et al. found dsDNA antibodies in 12% of patients [56], but another study failed to show such antibodies in ME/CFS (0.7%) [57].

Klein and Berg described anti-ganglioside antibodies in ME/CFS patients, but not in healthy controls [58]. In addition, they and others found phospholipid autoantibodies in ME/CFS patients [56,58,59] and antibodies against cardiolipin were described in 92–95% of ME/CFS patients in two studies [59,60] but only in 4% in another study [56]. Further autoantibodies against endothelial and neuronal cells were described in 30% and 16% of patients, respectively [56].

2.3.2. Antibodies against neurotransmitter receptors and neurotransmitter

Antibodies against the muscarinic M1 acetylcholine receptor (AChR) were reported in ME/CFS patients and were associated with muscle weakness [54]. Evidence for a functional role of these antibodies comes from a PET study showing reduced binding of a M AChR ligand in brain in antibody positive ME/CFS patients [61]. Antibodies against ß1 and ß2 adrenergic receptors (AdR) and M2/3 AChR were described in postural tachycardia syndrome, characterized by an increased heart rate in the absence of significant hypotension, as well as in orthostatic hypotension. This finding is of relevance for ME/CFS as 11–40% of ME/CFS patients concurrently suffer from postural orthostatic tachycardia syndrome (POTS) [[62][63][64][65]]. In a study from our group, elevated autoantibodies against both ß2-AdR and M3/4 AChR were found in a subset of ME/CFS patients compared to healthy controls [53]. A high correlation was found between levels of ß2 AdR autoantibodies and elevated IgG1–3 subclasses, activated HLA-DR+ T cells and thyroid peroxidase autoantibodies and ANA. The association of ß2 AdR autoantibodies with immune markers suggests an activation of B and T cells expressing ß2 AdRs. Further, disturbance of the AdR and M AChR function may explain symptoms of autonomic dysregulation in ME/CFS.

No differences between ME/CFS patients and controls were found in levels of autoantibodies directed against receptors for angiotensinendothelinmu-opioid, serotonin and dopamine [53,54]. However, autoantibodies against serotonin have been associated with ME/CFS [56,58].

2.3.3. Other autoantibodies

The IgM response against autoantigens formed by oxidative or nitrosative damage was studied by Maes et al. [66]. Autoantibodies directed against these neo-antigens, comprising oleic, palmitic and myristic acidS-farnesyl-l-cysteine, by-products of lipid peroxidation, e.g. malondialdehyde, and N-oxide modified amino acids, e.g. nitro-tyrosine and nitro-tryptophan, were significantly higher in ME/CFS patients than in controls. In addition, they observed that the level of these autoantibodies correlates with severity of illness and symptoms. Although increased IgM antibodies against these oxidatively damaged antigens were shown in major depression, too, a higher immune response was found in ME/CFS [67].

2.4. Soluble markers of autoimmunity

Autoimmunity is associated with enhanced levels of circulating inflammatory cytokines playing an important role in the pathogenesis of autoimmune diseases [68]. Elevated levels of cytokines related to Th1- as well as Th2-driven responses were reported for ME/CFS in several studies [42,[69][70][71][72][73][74]]. Further cytokine levels in ME/CFS were associated with severity and duration of illness [[72][73][74]]. However, alterations in cytokine profiles in ME/CFS were not found in all studies [75,76].

Elevated levels of B lymphocyte activating factor (BAFF) were described in a variety of autoimmune diseases including RA, SLE and pSS [77]. BAFF regulates the survival and maturation of B cells and mediates the IL-10 production of regulatory B cells [78,79]. Elevated levels of BAFF were shown in a subset of patients with ME/CFS in comparison to healthy controls [80]. As the gene expression of the BAFF receptor (TNFRSF13C) is reduced in ME/CFS, increased serum BAFF levels may represent a compensatory mechanism [37]. Interestingly, elevated serum BAFF levels correlated with the autoantibody production in RA, SLE and pSS [81]. In ME/CFS an association between BAFF and autoantibodies was not described so far.

Activin A and B, members of the Transforming Growth Factor β family, are involved in the control of inflammation and muscle mass [82]. Elevated levels of activin B as well as an elevated ratio of activin A or B to the binding protein follostatin in ME/CFS patients were demonstrated in a recent study [83]. An association of increased activin A with inflammatory bowel disease, RA, and asthma was already shown [82].

CD26 is a peptide-cleaving enzyme associated with immune regulation. In various autoimmune diseases, such as MS, Grave’s disease, and RA increased numbers of CD26 T cells were found in inflamed tissues and peripheral blood [84]. Fletcher et al. reported a higher frequency of CD26 expressing CD2+ lymphocytes in ME/CFS, but a decreased expression level on T and NK cells [85]. Further, they observed a reduction of the soluble CD26. Reduced serum CD26 levels were also reported for SLE and RA showing an inverse correlation with disease activity [84]. Low CD26 expression on PBMCs in ME/CFS was shown to correlate with reduced post-exercise muscle action potential, increased exercise- mediated lipid peroxidation, reduced quality of life and enhanced pain [86].

Other serum factors, frequently elevated in autoimmune disease like sCD30, sCD23, soluble cytotoxic T lymphocyte-associated antigen-4 (sCTLA-4) or the soluble IL-2 receptor (sIl-2R) are not described in ME/CFS so far [[87][88][89][90][91][92]].

2.5. Genetic variants associated with autoimmunity

It is well established that certain HLA alleles are associated with autoimmune diseases. Smith et al. showed an increased prevalence of the class II major histocompatibility complex HLA-DQB1  01 allele in ME/CFS patients [93]. Two others variants of HLA-DQB1 in combination with two RAGE-374A variants were associated with ME/CFS [94]. In another study the interaction of killer cell immunoglobulin-like receptors (KIRs) and their HLA class I epitopes were studied. An excess of KIR3DL1 and KIR3DS1 missing their HLA-Bw4Ile80 binding motif was shown in ME/CFS, leading potentially to an ongoing activation [95].

In the last years, genome-wide association studies revealed variants of various genes with either gain- or loss-of-function that are associated with the risk to develop autoimmune diseases. These single nucleotide polymorphisms (SNP) in receptors, enzymes or transcription factors play a role in B cell activationT cell development, activation and proliferation, and cytokine signaling which are crucial in autoimmune diseases [[96][97][98][99][100]]. Further, it is becoming increasingly clear that elements of the non-coding genome regulate a variety of normal immune functions and that dysregulation of enhancer elements or long non- coding RNA may play a key role in autoimmunity [101]. So far only polymorphisms in cytokine as well as toll-like receptor signaling pathways and complement cascade were studied showing an association with ME/CFS [102,103]. Due to its regulation of the inflammatory response the glucocorticoid receptor gene NR3C1 has gained interest. Several variants (SNPs) within NR3C1 gene were shown to be significantly associated with ME/CFS [104,105].

2.6. Energy metabolism and autoimmunity

Immunometabolism represents the interface between immunology and metabolism and is an exciting emerging field of research in autoimmunity [[106][107][108]]. The metabolic requirements of immune cells depend on their state of resting or activation and differentiation. Their activation results in a metabolic switch to aerobic glycolysis in order to provide enough energy and bio-precursors to meet the requirements for supporting rapid cell proliferation and immune functions. A growing body of evidence suggests that energy metabolism is crucial for the maintenance of chronic inflammation, not only in terms of energy supply but also in the control of the immune response through metabolic signals [106,107]. It has been suggested that disturbances in this intricate metabolic-immune cross-talk may be closely linked with and contribute to autoimmunity, although the precise pathomechanisms involved still remain to be elucidated [107,108]. It is also striking that several glycolytic enzymes act as autoantigens in rheumatic inflammatory disorders [109], although their role in ME/CFS remains unclear.

The profound and debilitating fatigue experienced by ME/CFS individuals led to the hypothesis that energy metabolism may be dysregulated. Defects in mitochondrial function in ME/CFS were shown in various studies from our group and others [[110][111][112][113]]. Metabolic profile had revealed disturbances related to energy, amino acids, nucleotidesnitrogen metabolism and oxidative stress in ME/CFS [[114][115][116][117][118][119]]. A metabolic shift toward aerobic glycolysis resulting in insufficient tricarboxylic acid (TCA) cycle and inadequate ATP production was reported recently, although the underlying basis has yet to be established [116,119]. Interestingly, the 2016 Fluge et al. study points to a secondary metabolic change driven by a serum factor in ME/CFS patients [116].

As dysfunctional metabolic pathways can directly influence and exacerbate defective immune responses, establishing the bioenergetic metabolism status of the different subsets of immune cells in ME/CFS has become a topic of increasing interest.

2.7. Comorbidity with autoimmune diseases

Comorbidity of ME/CFS with various autoimmune or immune-mediated diseases including fibromyalgia (FM), Hashimoto’s thyroiditis and POTS is observed (Fig. 2). Especially for FM there is considerable overlap with up to 77% of patients fulfilling disease criteria for both ME/CFS and FM [120]. FM is characterized by chronic widespread pain and is common in autoimmune diseases with around 50% of prevalence in patients with RA and SLE [121,122]. According to the modified ACR 2010 criteria FM has an overall estimated prevalence of 5.4%. In a recent study from our group analyzing clinical subgroups in a large Spanish ME/CFS cohort was reported FM comorbidity ranging from 26% to 91% [123]. In another study including patient cohorts from Norway, UK and USA, a comorbidity for ME/CFS and FM of 30% was observed [124]. In a similar manner Hashimoto’s thyroiditis characterized by elevated antibodies against thyroid peroxidase is frequent in autoimmune disease, whereas the overall prevalence is around 0.8% in the general population [125]. Hashimoto’s thyroiditis is found in 17–20% in ME/CFS patients [53,123]. Moreover, 11–40% of ME/CFS patients suffer from POTS [[62][63][64][65]]. Interestingly, for both disorders elevated frequencies of autoantibodies directed against AdRs and M AChRs were shown [53,[126][127][128]]. Furthermore, a substantial number of ME/CFS patients have a family history of autoimmune diseases [129,130].

Fig. 2

3. Therapies targeting autoimmunity in ME/CFS

First clear evidence for a pathogenic role of autoantibodies in ME/CFS comes from two clinical trials with the monoclonal anti-CD20 antibody rituximab [129,131]. Upon depletion of CD20+ B cells with rituximab, a monoclonal antibody directed against the B cell surface protein CD20, approximately 60% of patients experienced a partial or complete, and in some patients sustained clinical remission (Table 2). The delayed onset of response with a median of approximately 4 months in both trials suggests that clinical effects are not directly mediated by depletion of CD20+ B cells, but by diminishing short-lived antibody-producing plasma cells arising from CD20+ memory B cells, followed by subsequent wash-out of autoantibodies. Results from a multicenter controlled trial with rituximab are awaited in spring 2018.

Table 2. Clinical trials targeting autoimmunity in ME/CFS.

DosageStudy designPatients (n)EvaluationOutcomeRefs.
Intravenous IgG
1 g/kg/m2

RCT28FI & SRNo difference[133]
2 g/kg/m2

RCT49FI & SRFollow-up m3: 43% vs. 12%[134]
0.5 g/1 g/2 g/kg/m2

RCT99FI & SRNo difference[135]
1 g/kg/m2

RCT70 (adolescents)FIFollow-up m6: 72% vs. 44%[136]
Rituximab
500 mg/m2

RCT30FI & SRImprovement 67% vs. 13%[131]
500 mg/m2 6×Single arm29FI & SRImprovement 62%[129]
Ongoing Trials
Cyclophosphamide (Endoxan®)Fluge et al., unpub.
Immunoadsorption[137]

Abbreviations: RCT = Randomized controlled trial; FI=Functional Improvement; SR = Symptom reduction, assessed by questionnaires; unpub.: unpublished data.

Few other treatment modalities targeting autoimmunity were evaluated in clinical trials in ME/CFS (Table 2). High dose intravenous IgG therapy is efficacious in autoantibody-mediated diseases. Several intravenous IgG studies were performed in ME/CFS during the 80’s with two randomized controlled trials with positive and two with a negative outcome [132]. Preliminary data from an ongoing trial in Norway with cyclophosphamide suggests therapeutic efficacy of this broadly immunosuppressive drug (Fluge et al., unpublished data). Immunoadsorption is an apheresis in which IgG is specifically removed from plasma resulting in clinical improvement in various types of autoimmune disease. We performed a pilot trial in 10 patients with ME/CFS and observed first evidence for efficacy [137].

4. Conclusion

There is compelling evidence that autoimmune mechanisms play a role in ME/CFS. However clinical heterogeneity in disease onset (infection versus non-infection triggered), presence of immune-associated symptoms, and divergent immunological alterations point to the existence of subgroups of ME/CFS patients with possibly different pathomechanisms. Therefore, it is important to identify clinically useful diagnostic markers to select patients with autoimmune-mediated disease for clinical trials. The search for autoantibodies is of great importance enabling to develop potential biomarkers for diagnosis and providing a rationale for therapeutic interventions. Encouraging results from first clinical trials warrant larger studies with rituximab and other strategies targeting autoantibodies.

Funding

This review is based upon work from European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) as part of Cost Action CA15111 supported by the EU Framework Program Horizon 2020. Website: http://www.cost.eu/COST_Actions/ca/CA15111.

Author contributions

FS and CS were responsible for the first draft of the protocol, which was critically reviewed, further developed and approved by all authors.

Declaration of competing interests

JB reports personal fees from ALBAJUNA THERAPEUTICS, S.L., outside the submitted work; CS has received grant support for clinical trials and research from Fresenius, Shire, Lost Voices, SolveME, MERUK, IBB, and speaking honoraria from Octapharma and Shire. FS, EC, JCM, SS and MM have no conflict of interest to declare.

Acknowledgements

Not applicable.

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Published by Elsevier B.V.

ME/CFS and autoimmunity

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The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/cfs)

Molecular Neurobiology volume 49, pages741–756(2014) Cite this article

Abstract

The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses. A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies. The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host’s immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia.

ME/CFS and homeostatic drive

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A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome

PLEASE NOTE: THIS VERSION OF THE ARTICLE CONTAINS THE FOLLOWING CORRECTIONS:

16 Jun 2014: The PLOS ONE Staff (2014) Correction: A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome. PLOS ONE 9(6): e100355. https://doi.org/10.1371/journal.pone.0100355 View correction

3 Apr 2014: The PLOS ONE Staff (2014) Correction: A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome. PLOS ONE 9(4): e94161. https://doi.org/10.1371/journal.pone.0094161 View correction

Introduction

The hypothalamic-pituitary-adrenal (HPA) axis, a key component in the body’s stress response, serves to articulate changes in a broad range of homeostatic regulators as a function of environmental cues. Such cues can consist of both physical stressors (injury, infection, thermal exposure) and psycho-emotional stressors (frustration, fear, fight or flight decisions). Instantiation of this survival program is accomplished through controlled modulation of the neuroendocrine and immune systems, as well as the sympathetic nervous systems [1][3]. Considering its function as a broad-reaching integrator of major physiological systems, it is no surprise that numerous chronic conditions have been associated with abnormal regulation of the HPA axis, including major depressive disorder (MDD) [4][5], post-traumatic stress disorder (PTSD) [6][8], Alzheimer’s disease [9], Gulf War Illness (GWI) [10][12], and chronic fatigue syndrome (CFS) [13][15]. When compared to non-deployed veterans, Golier et al. [10] found that symptomatic Gulf War veterans without psychiatric illness, as well as veterans with PTSD alone, showed significantly greater cortisol suppression to dexamethasone (DEX) suggesting markedly enhanced negative feedback along the HPA axis. Further study by these same investigators indicated that this might be due to a significantly attenuated ACTH response by the pituitary in veterans with GWI without PTSD [11][12]. A similar suppression of cortisol response to DEX was found in CFS subjects by Van Den Eede et al. [13] with this being further exacerbated by oestrogen intake. With regard to HPA circadian dynamics, CFS subjects were found to exhibit significantly increased adrenal sensitivity to ACTH and marginally increased inhibitory feedback during the nocturnal period when compared with control subjects and CFS subjects comorbid with fibromyalgia (FM) [14][15]. Conversely the pain-dominant CFS-FM subjects showed significantly blunted cortisol inhibitory feedback. While evidence such as this implicates abnormal regulation of HPA function leading to chronic hypocortisolic and hypercortisolic states in these illnesses, the genesis of this dysregulation is unclear.

Previously we investigated the possibility that some of these pathological states may coincide with naturally occurring alternate homeostatic stable states [16]. These “backup programs” would offer a way of maintaining homeostatic control in crisis situations at the cost of reduced function. The existence of such multiple stable states is characteristic of systems that incorporate feed-forward and feedback mechanisms. Feed-forward loops in biology play the crucial role of driving rapid acute responses, while feedback loops will generally limit the extent of a response. Both will also drive complex dynamic behavior, including differentiation and periodicity [17]. While small perturbations may force temporary departures, these systems return to their original resting states once these perturbations are removed. If however, the perturbation is of significant strength and duration, the system may be incapable of returning to its normal operating regime and instead may assume a new alternate resting state. Knowledge of the system dynamics can allow us to map these different stable states and several mathematical models of the HPA exist [16][18][22]. So far, only one such model is known to accommodate multi-stability in the dynamic behavior of the HPA axis. It does so via the addition of a feed-forward mechanism involving dimerization of the glucocorticoid receptor (GR) complex [22] (Figure 1). In this process glucocorticoid (GC) bound GRs form homodimers that translocate into the cell nucleus to bind DNA, up-regulating GR synthesis and producing a positive feedback loop. However, this model and the majority of other models do not extend beyond the physiological boundaries of the HPA axis itself and thus are limited in their predictive capabilities. As discussed in the following sections, HPA activity is intertwined with the behavior of the hypothalamic-pituitary-gonadal (HPG) axis and the immune system, among others, and this interplay should not be ignored when considering the number and nature of stationary states available to the overarching system. Our hypothesis is that these alternate regulatory regimes may facilitate the persistence of complex chronic illnesses like GWI and CFS. To evaluate the role of alternate homeostatic attractors in these illnesses we constructed a computational model of regulatory control linking the HPA, HPG and immune systems.

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Figure 1. Standard and extended HPA models.

(A) Standard HPA model. (B) HPA-GR model of Gupta et al. [22]. Integrated models (C) HPA-GR-Immune-HPGa for males, and (D) HPA-GR-Immune-HPGb, (E) HPA-GR-Immune-HPGc, (F) HPA-GR-Immune-HPGd, and (G) HPA-GR-Immune-HPGe for females. For (C) – (G) connections between the sex steroid EST and the HPG and HPA components change between stimulatory and inhibitory to capture the effects of the menstrual cycle.

https://doi.org/10.1371/journal.pone.0084839.g001

There is a substantial body of physiological and biochemical data for many biological systems describing the connectivity between molecular and cellular elements, the presence of recurring structural motifs and functional modules. For example, negative autoregulation, in which a transcription factor represses its own transcription, is a simple network motif observed in many transcription networks. While, numerous motifs have been found in biological networks (negative/positive autoregulation, coherent/incoherent and multi-output feed-forward loops, single-input modules and dense overlapping regulons) [17], data regarding the precise stoichiometry and kinetics within and between these multiple systems in humans is extremely limited. Obtaining many of these parameters in humans currently presents significant challenges associated with invasive sampling. As such, many existing models rely heavily on animal data as a source of kinetic parameters, or adopt general order of magnitude estimates when this data is unavailable. Using such estimates allows Ordinary Differential Equation (ODE) based models to provide detailed descriptions of transitory behavior, albeit for well-characterized systems. To broaden this scope and draw on the rich body of known molecular and cellular interactions in physiological and biochemistry, we have adopted the discrete logical network methodology proposed originally by Thomas et al. [23][24] and developed further by Mendoza and Xenarios [25]. By applying logic rules to a network of known interactions it is possible to identify the number of stable resting states, their type as well as their molecular and cellular description, without detailed knowledge of the response dynamics. Here detailed kinetic data is not required as working with connectivity alone allows useful qualitative insights regarding the stability of these systems. In this work we use this method to extend our previous analysis of human HPA axis dynamics by including its regulatory interactions with the neighboring HPG axis and immune system. This resulting mathematical model better represents the complexity of endocrine-immune interactions by supporting the detection and identification of alternate resting modes of the HPA-HPG-immune axis. Based on connectivity information alone, we show that multi-stability is easily obtained from these interacting systems. Moreover, we show that experimental data from our on-going studies of GWI and CFS show better alignment with these alternate resting modes than with the typical healthy homeostatic stable state. Ultimately, knowledge of such homeostatic modes could be used to identify promising applications of pharmaceutical, hormone and/or immune therapy that exploit the body’s natural dynamics to reinforce treatment effects.

Methods

Ethics Statement

All subjects signed an informed consent approved by the Institutional Review Board of the University of Miami. Ethics review and approval for data analysis was also obtained by the IRB of the University of Alberta.

An Integrative Multi-systems Model of the HPA-HPG-Immune System

There is a substantial amount of physiological data describing the HPA, HPG and immune systems as stand-alone entities. To a much lesser degree there also exists evidence for the mutual interactions between these systems. The following sections describe the experimental evidence used to infer the topology of an overarching HPA-HPG-immune interaction network (Figure 1).

The HPA Axis.

Activation of the HPA axis begins at the paraventricular nucleus (PVN) of the hypothalamus. Specifically, afferents transmitting stress related information in the brain converge on the medial parvocellular neurons of the PVN inducing the release of several peptides, including corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), into the pituitary hypophysial-portal circulation. The unique vascular system allows very small quantities of these hypothalamic hormones to act directly on their targets in the anterior pituitary without dilution by systemic circulation. CRH and AVP act in conjunction on membrane bound CRH-R1 receptors in the anterior pituitary to stimulate adrenocorticotropic hormone (ACTH) synthesis, and its rapid release into peripheral circulation. ACTH circulates to the adrenal cortex where it acts on the membrane bound MC2-R receptor to simulate the release of GCs (corticosterone in the rat, and cortisol (CORT) in humans and nonhuman primates). To regulate the stress response, GCs exert negative feedback at the hypothalamus and pituitary to inhibit further synthesis and release of CRH and ACTH, respectively [26]. This is the standard view of the HPA axis utilized in the majority of models (Figure 1 A). However, as noted by Gupta et al. [22] circulating glucocorticoids act via cytostolic GRs, which, unlike membrane bound receptors, dimerize (GRD) and translocate into the cell nucleus upon activation to up-regulate GR synthesis and interact with other relevant transcription factors, or GC-sensitive genes (Figure 1 B). Gupta et al. included this GR expression feed-forward loop at the pituitary, as it is a main driver of the HPA axis, and found a resulting bistability in the HPA system [22]. However, all nucleated cells possess GRs, as GCs influence practically every system in the body, suggesting this feed-forward loop may be important in other tissues beyond the HPA axis. As described below major systems affected by GCs include the HPG axis and the immune system.

The HPG Axis.

GCs have an inhibitory effect on the HPG axis, a central regulator of the reproductive system, at all levels [27][31]. Activation of the HPG starts from brain generated pulsatile signals that stimulate the preoptic area of the hypothalamus to produce gonadotropin-releasing hormone (GnRH). GnRH is secreted into the pituitary hypophysial portal bloodstream, which carries it to the pituitary gland, where it activates membrane bound GnRH-R receptors, resulting in the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into circulation. These gonadotropins flow to the gonads where they work synergistically to promote the secretion of the sex steroids. In males, LH binds to receptors on Leydig cells in the testes to stimulate the synthesis and secretion of testosterone (TEST). In females, LH activates receptors on Theca interna cells in the ovaries to stimulate the release of androstenedione, which is aromatized by granulosa cells to produce estradiol (EST), and progesterone (PROG). TEST negatively feeds back on the HPG to inhibit GnRH, FSH and LH secretion and synthesis [27]. This feedback mechanism is somewhat more complex in females where, depending on the phase of the female menstrual cycle, EST and PROG can exert either positive or negative feedback on the production and release of GnRH and the gonadotropins [30][32][33].

A lesser-known aspect is that several components of the HPG axis exert reciprocal effects on the HPA axis [27][28][30]. Testosterone exhibits an inhibitory effect on all levels of the HPA [27] (Figure 1 C), whereas EST and PROG can serve to stimulate or inhibit the HPA axis depending on menstrual cycle phase, or phase of life [28]. These affects may be mediated through changes in adrenocorticoid synthesis, stress-induced ACTH and GC release, and CRH and AVP synthesis in the PVN, by direct activation of oestrogen and androgen receptors along the HPA or via interaction between GRs and sex steroid receptors to regulate transcription [27][28][30]. Thus, an interactive functional crosstalk exists between the HPA and HPG axes, which cannot be ignored when investigating HPA axis regulation and dysfunction. Mutual inhibition between the HPA and HPG (Figure 1 C) was considered standard for males. However, as it is not clear whether the EST and PROG inhibition/stimulation of the HPA occurs in coordination with the inhibition/stimulation of the HPG, these cases were explored for females alone as separate alternative models of the HPA-HPG interaction (Figure 1 D–G) in addition to the model considered for males.

A Simple Model of the Immune System.

While not typically considered part of the neuroendocrine system, the immune system plays a very important role in regulating the HPA axis. Here we base our simplified immune system upon our previous work detailing the communication network of the immune response [34]. Cells of the innate immune response (ICells), including mononuclear phagocytes, such as macrophages, and dendritic cells, natural-killer (NK) cells, endothelial cells and mucosal epithelial cells, communicate via the release of numerous cytokines. Cytokines that regulate the innate immune response (IIR) include interleukin (IL) -1, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α), and can also include IL-12, a primary mediator of early innate immunity. Primarily, these signals serve to activate and recruit other ICells, which in turn produce more cytokines. IL-15, which stimulates proliferation of NK cells and effector T-lymphocytes, can also be considered as part of the IIR as well as IL-23, an important inflammatory signal contributing to the Th17 response against infection.

IIR signals can also serve to prime helper T cells towards a Th1 type adaptive immune response (T1Cell). This response produces Th1 proinflammatory cytokines (T1Cyt) including IL-2, interferon-gamma (IFN-γ), and tumor necrosis factor beta (TNF-β), which further activate ICells, while suppressing the Th2 adaptive immune response (T2Cell). The T2Cell is responsible for the production of the Th2 anti-inflammatory cytokines (T2Cyt) IL-4, IL-5, IL-10 and IL-13, which have important anti-inflammatory and immunosuppressive activities, and serve to inhibit the activity of T1Cell and ICells.

Cytokines can also serve as mediators between the immune and endocrine systems. Between the HPA and the immune network there exists a mutual crosstalk [35][37] (Figure 1 C–G). The IIR and T1Cell cytokines selected here serve to stimulate the HPA axis at all levels [35][37]. CORT, in turn, acts to suppress the activity of ICells (specifically NK cells [38], and DC cells [39]), and the T1Cell [40] causing a shift from the inflammatory to the anti-inflammatory response [35][36][41]. The interaction between the HPG and the immune system is complex and sexually dimorphic, and is still an active field of research. However, at a general coarse level of description TEST serves to stimulate the development of the Th1 response [42] (Figure 1 C), whereas EST inhibits the Th1 response causing a shift towards the Th2 anti-inflammatory response [42][43]. The reciprocal crosstalk from the immune system to the HPG is equally intricate. In broad terms this conversation is communicated via T1Cyt. Receptors for TNF-α and IFN-γ are expressed in testicular Leydig cells and there is evidence that these cytokines can directly inhibit testosterone production [44]. TNFα also decreases the release of GnRH in the hypothalamus and LH in the pituitary gland in both males [44] and females [45] eventually leading to a decrease in sex steroid levels. As such, we model the T1Cyt as inhibiting GnRH and LH/FSH in both male and female models.

A Discrete State Representation

Following the methods of Thomas et al. [23][24], and more recently Mendoza and Xenarios [25], the neuroendocrine-immune system was represented as a connectivity model consisting of interconnected molecular and cellular variables with three discrete states: −1 (inhibited), 0 (nominal) and 1 (activated). According to this type of model the current state of all variables in a system is described by a state vector , such that:(1)where  is the state of the ith variable of the N variable system at time t. The image vector  describes the preferred state towards which the system evolves in the next time increment. The state value of the image vector for the ith variable is determined from its current state and a set of balanced ternary logic statements based on the current value of variable and the mode of action (i.e. activate or inhibit) of the neighboring input variables. These logic statements are expressed as follows (Eq. 2):

(2)where the ∇, ∨, and ¬ symbols are ternary HIGH/LOW PASS, OR and NOT operators,  is the state of the ith variable’s jth activator, is the state of the ith variable’s kth inhibitor. The ternary operators given in Equation (2) are described in further detail in Table 1Table 2Table 3. The first entry in Equation (2) is used when the variable possesses activators and inhibitors, the middle when the variable has only activators and last when the activator has only inhibitors.

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Table 1. Ternary HIGH/LOW PASS operator.

https://doi.org/10.1371/journal.pone.0084839.t001

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Table 2. Ternary OR operator.

https://doi.org/10.1371/journal.pone.0084839.t002

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Table 3. Ternary NOT operator.

https://doi.org/10.1371/journal.pone.0084839.t003

Applying Equation (2) to each variable in the model for the mth state of the system, , defines the image vector  for that state. With  defined, the system may be updated asynchronously (allowing only one variable to change at a time) following the generalized logical analysis of Thomas et al. [23][24]. According to this method the ith variable of the mth state vector  is moved one step towards its preferred image  (e.g. If   = −1 and   = 1, then  is set to 0). Thus, for each current state of the system there are potentially several subsequent states towards which it may asynchronously evolve.

The number of states, and the values they can be assigned, determine the total number of states available to the model system. With the ternary logic used here, a model of N variables possesses 3N states. As a result, the number of states increases rapidly as new variables are added. By analyzing all possible states of the system a temporal sequence of states may be discerned. To interpret the results, each state of the system can be represented as an element in a graph. The evolution from one state to a subsequent state can be represented as a directed edge between the two states in this graph. Representation of the state trajectories in this fashion makes it possible to draw on the concepts and tools of graph theory for analysis of the system dynamics. Steady states are defined as those states for which the image vector is the same as the current state vector; in other words the state possesses an out degree of 0.

Experimental Data

Experimental data obtained as part of a larger on-going study investigating changes in cytokines and hormones in GWI and CFS groups was used as a basis for comparison with the predicted resting states. Previous work with the CFS datasets by Broderick et al. presents full repeatability statistics on the cytokine panels using n = 9 CFS, and n = 12 controls [46]. Significant changes in correlation patterns linking immune gene sets in CFS with n = 39 CFS and n = 35 controls) [47]. Similarly in GWI we observed significant changes in association patterns (mutual information) for n = 9 GWI and n = 11 controls across 3 points in time [48] for salivary cortisol and plasma, serum or culture supernatants expression of neuropeptide Y (NPY), IL-1a, IL-5, IL-6, IL-10, TNF-α, IFN-γ and soluble CD26 (sCD26). Larger sample sizes are used in this work to further improve the statistical power and resolution in identifying characteristic differences between subject groups.

GWI.

Cytokine profiles and endocrine measures were obtained for 27 GWI and 29 HC subjects recruited from the Miami Veterans Administration Medical Center. Subjects were male with an average age of 43 years and BMI of 28. Inclusion criteria was derived from Fukuda et al. [49], and consisted in identifying veterans deployed to the theater of operations between August 8, 1990 and July 31, 1991, with one or more symptoms present after 6 months from at least 2 of the following: fatigue; mood and cognitive complaints; and musculoskeletal complaints. Subjects were in good health prior to 1990, and had no current exclusionary diagnoses [50]. Collins et al. [51] supports the use of the Fukuda definition in GWI. Control subjects consisted of gulf war era sedentary veterans and were matched to GWI subjects by age, body mass index (BMI) and ethnicity. Additional details regarding this cohort and the laboratory assays performed are available in Broderick et al. [48]. Data will be made freely available upon request.

CFS.

Levels of cortisol (CORT) and estradiol (EST) measured in peripheral blood were obtained from the Wichita Clinical dataset [52] for a group of 39 female CFS subjects and 37 Healthy controls (HCs) with an average age of 52 years and an average body mass index (BMI) of 29. Additional details of this cohort and the laboratory assays performed may be found in work previously reported by our group [53][54]. Multiplex cytokine profiles were obtained in plasma from a separate but demographically comparable cohort of 40 female CFS subjects and a group of 59 healthy female matched control subjects studied by our group at the University of Miami [55]. Average age in this cohort was 53 years with an average BMI of 26. Profiling of cytokine concentrations was performed in morning blood plasma samples using an enzyme-linked immuno-absorbent assay (ELISA)-based assay. Details of this protocol and results of a comparative analysis of cytokine expression patterns are available in Broderick et al. [55]. In both studies a diagnosis of CFS was made using the International Case Definition [50][56]. Exclusion criteria for CFS included all of those listed in the current Centers for Disease Control (CDC) CFS case definition, as well as psychiatric exclusions, as clarified in the International CFS Working Group [56]. Data will be made freely available upon request.

Statistical Analysis

Brown’s theoretical approximation [57] of Fisher’s statistics was used to calculate the significance of alignment between experimental data and a given model predicted state. Fisher’s method, a meta-analysis technique, combines probabilities to obtain the overall significance P of a set of p-values obtained from independent tests of the same null hypothesis. The combined χ2 statistic,(3)where N is the number of measureable variables and pi is the corresponding p-values under the null hypothesis, has a χ2 distribution with 2N degrees of freedom assuming that the performed tests are independent. As the molecular variables of the endocrine and immune system interact with one another, as evidenced by the above connectivity diagrams, they are not independent. As a result, direct application of this test statistic is invalid, since the assumption of independence is violated. Brown [57] suggested a method for combining non-independent tests. If the tests are not independent, then the statistic T0 has mean m = 2N and variance (σ2) given as,(4)where pi and pj are the p-values for each test and the covariance (cov) is calculated as,(5)with ρij being the unadulterated correlation between variable i and variable j. Finally, the overall significance P of a set of non-independent tests is calculated using the statistic T which under the null hypothesis follows the central χ2 distribution, where T = T0/c with 2N/c degrees of freedom and c = σ2/4N.

Here, we test if each experimental measure aligns with a given model predicted state. Our null hypothesis is that the experimental measures do not align. p-values for individual variables, pi, are calculated using two-sample t-tests between ill subjects and healthy controls. Where model predictions give a variable as high (+1), ‘right-handed’ one-tailed test are used, whereas a ‘left-handed’ test was used when model predictions are low (−1), to give the probability of obtaining the predicted value when the null hypothesis is true. For the case where the model predicts normal behavior for a variable (0) a two-tailed t-test is used. However, the p-value from the two-tailed test, ptwo-tail, gives the probability that there is an observable difference between illness and control, which is the null hypothesis. To rectify this, when comparing to a model predicted variable of 0 we take the p-value to be pi = 1 − ptwo-tail, giving the probability of obtaining the predicted value when the null hypothesis is true.

All cohort data was normalized using a Log2 transformation before T-tests and correlation calculations were performed. The unadulterated correlation values ρij between two variables i and j were calculated in healthy subjects as the pairwise Pearson’s linear correlation coefficient between variables. The above-mentioned experimental data was compared against model predictions based on the five measureable variables, namely TEST/EST, CORT, IIR, T1Cyt, and T2Cyt. Where model variables represent an aggregate set of markers each experimentally measured constituent marker was compared individually to the model predicted value. For example, T1Cyt is composed of IL-2, IFNγ and TNFβ, therefore 3 individual p-values were calculated based on the predicted value of T1Cyt.

These significances of alignment are best visualized with a Sammon projection of the aggregated P value as distances between the clinical data and the predicted model values. Non-metric multidimensional scaling using Sammon’s nonlinear mapping criterion was used to project the P value distances onto a 2 dimensional plot. The aggregate P values between predicted model states were determined via Brown’s method above. Where values between predicted states were found to disagree p-values for individual variables, pi, were taken as 1. Where values between predicted states were found to agree, pi was assigned a standard minimum value for significance of 0.05 to avoid numerical instability in the calculation of T0.

Results

Stable States in the HPA Models

Application of the discrete state representation to the basic stand-alone HPA model (Figure 1 A) generated 27 system states, and failed to produce multiple stable resting states (Figure 2). The only stable state found consisted of baseline values (SS0) for all state variables. This result is consistent with previous ordinary differential equation models based on this minimal representation of the HPA axis that produce solutions converging to a single fixed state [18].

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Figure 2. Steady states of standard and extended HPA models.

White – nominal state (0); Green – high state (1); Red – low state (−1); Grey – N/A to the model.

https://doi.org/10.1371/journal.pone.0084839.g002

Discrete state representation of the HPA-GR model (Figure 1 B) generated 243 system states. Of these, 2 system states possessed no outbound edges and were stable attractor steady states (Figure 2). In the first steady state all state variables assumed nominal values (SS0) whereas the second steady state corresponded to activation of state variables GRD and GR with suppression of ACTH and CORT (SS1). This hypocortisolic solution is consistent with that obtained by analysis of the ordinary differential equation model of the HPA-GR system proposed by Gupta et al. [22] and Ben Zvi et al. [16]. Further models by Walker and colleagues, based on Gupta et al. [22], have shown natural oscillatory rhythms in the HPA axis [19][21]. While these models make the significant association between delayed feedback and ultradian rhythms, the oscillations around baseline are small and consistent, representing a single resting behavior. As our discrete state representation considers normal resting values as 0, with −1 and 1 representing significant perturbations, minor deviations are not captured and therefore such small oscillatory behavior can be considered similar to our nominal steady state (SS0). This lower resolution allows for a greater breadth of study, accommodating the inclusion of multiple systems of interest, which previously have not been considered in modeling studies.

Combining the HPA-GR axis with the HPG axis and immune system (Figure 1 B–G) altogether produced 4,782,969 system states. For the male HPG (model a) (Figure 1 C), and three of the four female HPG models (models b, d and e) (Figure 1 D, E, G) five steady states were identified (Figure 2). One stable state is characterized by nominal values for all variables (SS0), which corresponds to the typically normal resting state of the system. The first alternate state (SS1) displays low ACTH with high GRD and GR, while the second (SS2) has inhibited innate and Th1 immune responses (low ICell, IIR, T1Cell, and T1Cyt), with increased Th2 activity (high T2Cell and T2Cyt). The third stable state (SS3) appears to be a combination of SS1 and SS2 with low ACTH, ICell, IIR, T1Cell and T1Cyt, and high GRD, GR, T2Cell and T2Cyt. The final state (SS4) presents with hypercortisolism, suppressed TEST and a shift towards the Th1 immune response (low T2Cell, T2Cyt, GnRH, LH/FSH and TEST/EST, and high CORT, GRD, GR, T1Cyt and T1Cell). The persistently low CORT state seen in the previous stand-alone HPA models of Gupta et al. [22] and Ben Zvi et al. [16] was not recovered here. Instead, CORT was expressed at a nominal or high value for all predicted states. SS1 most closely resembles the results of Gupta et al. [22], and Ben Zvi et al. [16], however these previous models only considered a single regulator of CORT, namely ACTH. The lack of a predicted hypocortisolic state in SS1 here can be attributed to the interplay of multiple regulators of CORT (ACTH, IIR, TEST/EST, and T1Cyt). Inclusion of additional regulators is not expected to further alter this state.

In the final female HPG model (model c) (Figure 1 F), corresponding to the ovulation phase, these same five states were recovered along with six new additional states (Figure 2). In the first three additional states the HPA axis and innate immune response are suppressed with low CRH, ACTH, CORT, ICell and IIR, while the HPG and anti-inflammatory response are raised with high T2Cell, T2Cyt, GnRH, LH/FSH and EST. The difference between the three states is noted in the level of glucocorticoid receptor response, GR and GRD, which together take values of low (SS5), nominal (SS6) and high (SS7). The remaining three additional states all give suppressed HPA (CRH, ACTH, and CORT) and lowered T1Cell activity, with high HPG activity (GnRH, LH/FSH and EST), and are again differentiated by their glucocorticoid receptor levels (GR, GRD): low (SS8), nominal (SS9) and high (SS10).

Overall, inclusion of the simplified immune system and the HPG works to regulate CORT levels in the HPA axis. The male HPG (HPG model a), and the majority of female HPG configurations (HPG models b, d and e), serve to produce either nominal values of CORT, with the potential of a shift towards Th2 activation (SS2 and SS3), or a hypercortisolic state with low TEST/EST and a shift towards Th1 (SS4). Only connections associated with the female gender (HPG model c) were responsible for the emergence of a natural hypocortisolic state (SS5 – SS10). This hypocortisolic state comes with high EST and may have a shift towards Th2 activation in the immune system.

Comparison of GWI and CFS to Predicted States

Application of Brown’s meta-analysis method allowed for the calculation of a combined P-value comparing the experimental data with the predicted stable states, allowing for the alignment between different predicted stable states to be ranked. As experimental measures allowed for comparison with only five variables (TEST/EST, CORT, IIR, T1Cyt, and T2Cyt) several of the predicted stable states resulted in the same experimental profile and resulting combined P-value despite being distinct states (e.g. SS0 and SS1 both show nominal values for the five measureable variables).

To compare to our model the difference between steroid and cytokine levels recorded in male Gulf War veterans with GWI and HCs were compared to the steady state values predicted by the male variant of the HPA-GR-Immune-HPG model (model a). Comparison to the nominal states (SS0/SS1) showed poor alignment, PSS0/SS1 = 0.82, suggesting that the GWI profile cannot be considered the same as nominal behavior. Alignment with states presenting a shift towards Th2 immune activation (SS2/SS3) showed better alignment, PSS2/SS3 = 0.38, although with low significance. The final state, displaying hypercortisolism, low TEST and a shift towards Th1 immune activation (SS4), yielded the best alignment, PSS4 = 0.30, again however, with a low overall significance. These alignments are illustrated via the Sammon plot shown in Figure 3A.

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Figure 3. Sammon projection of illness and model predicted states.

Axes represent arbitrary units such that the relative Euclidean distance between points approximates the significance of alignment P-value between states, as shown by connecting lines. (A) Male GWI. (B) Female CFS.

https://doi.org/10.1371/journal.pone.0084839.g003

The difference between steroid and cytokine levels of female CFS subjects and HCs were compared to the steady state values predicted by the female variants of the HPA-GR-Immune-HPG models (model b-e). Again, alignment with states presenting nominal changes in measureable variables (SS0/SS1) was poor, PSS0/SS1 = 0.83, supporting that CFS is distinctly different from normal behavior. The Th2 shifted immune profile states (SS2/SS3) showed a significant alignment, PSS2/SS3 = 0.04, suggesting Th2 activation in CFS. This is further supported by low alignment with the Th1 immune activated state, with hypercortisolism, and low EST (SS4), PSS4 = 0.28. Improved alignment is seen in states with a shift towards Th2, coupled with hypocortisolism, and high EST (SS5/SS6/SS7), PSS5/SS6/SS7 = 0.02, suggesting that these features contribute to the CFS profile. This is also supported by low alignment with states only presenting hypocortisolism and high EST with no immune activation (SS8/SS9/SS10), PSS8/SS9/SS10 = 0.60. These alignments are visualized in Figure 3B.

Discussion

The existence of multiple stable states is a prime characteristic of systems incorporating feed-forward and feedback mechanisms, and plays a critical part in guiding the complex dynamics observed in biology. These alternate stable regulatory regimes occur due to the feed-forward and feedback mechanisms within the system and may allow escape routes for survival of an insult and provide support in the medium or long-term to what is equivalent to an uneasy cease-fire or adaptive compromise. Examples of such compromises in functional status in exchange for survival include vasovagal response to decreased blood pressure and syncope (“fainting”) [58]. From an evolutionary perspective it would be advantageous for a pathogen to establish an adaptive relationship with the host. As naturally occurring alternate states of homeostasis are inherently stable, exploiting these regimes could be an advantageous way for a pathogen to establish long-term chronic infection, in essence using the body’s own homeostatic drive to maintain the status quo. Deviations of persistent illness profiles from normal homeostatic states argue in favor of the continued presence of an initial aggravating factor or of lasting alterations to the regulatory circuitry imparted by the initial insult [59][60]. The latter would essentially modify the solution landscape resulting in new natural attractors. To explore this hypothesis, we constructed a simple but integrated model incorporating three of the body’s major regulatory axes: the HPA, the HPG and the immune system. Modeling the dynamic properties of these complex systems presents a significant challenge, as much of the detailed information describing in vivo kinetics in humans is unavailable. However, there is a very significant body of connectivity data describing the interactions between the molecular and cellular elements of these biological systems. To make use of this wealth of information we have applied a discrete state representation to the neuroendocrine immune system based solely on the biological connectivity found in the literature and a set of ternary logical rules. Using a discrete logic methodology proposed by Thomas [24], we demonstrated that the inclusion of feed-forward/feedback loops leads to multiple stable states. Indeed, addition of the positive feedback loop regulating glucocorticoid receptor dimerization (GR-GRD) to a basic model of the HPA axis generated an alternate homeostatic state characterized by high receptor expression and low circulating cortisol levels, a result found previously by Gupta et al. [22] and Ben Zvi et al. [16] using differential equation based models. So dependent is the natural emergence of these states on the regulatory wiring that inclusion of this receptor dimerization in a more complex HPA-Immune-HPG models resulted in the disappearance of this alternate hypocortisolic state through compensatory effects of these axes. Only when all three interacting axes were included was an alternate hypocortisolic condition recovered. Therefore while simple models require the inclusion of positive receptor feedback dynamics to produce multistability, these effects become inherent in more coarse, but comprehensive regulatory circuits, and receptor-level feedback becomes less of a contributor in the support of multiple attractor states. Coarse-grained but comprehensive models may suffice therefore in capturing physiologically relevant and clinically verifiable response dynamics.

Our analysis of these coarse grained models spanning across multiple regulatory axes highlighted the important role of gender in supporting a persistent hypocortisolic condition. Due to the suppressive actions of the male gonadal system in regulating itself and the HPA axis, a low cortisol steady state is never available to the male, at least theoretically at this level of detail. In women however, the combined effect of EST and PROG on the HPA still remains somewhat inconsistent [28][61] owing to the varying effects of these hormones during and after the menstrual cycle. EST is generally believed to stimulate the HPA axis during the menstrual cycle [61][63], however evidence indicates that in perimenopausal, menopausal or ovariectomized women the HPA axis response is inversely correlated with plasma EST levels suggesting an inhibitory effect [63][64]. This suggests that sex hormone regulation may change in feedback polarity and act as both inhibitor and activator of the HPA axis. For this reason HPA-HPG interaction in women will in theory readily support the presence of a stable hypocortisolic condition when HPG axis regulation inhibits the HPA axis while stimulating itself.

In addition to sex hormone regulation, interaction with the immune system also appears to play a significant role in determining abnormal cortisol levels. In our coarse-grain models, cortisol exerts a suppressive action on the innate immune system and the Th1 adaptive immune response. Conversely, positive feedback by certain components of the immune system promotes increases in cortisol levels, which support a hypercortisolic steady state. While, inclusion of the glucocorticoid receptor dimerization (GR-GRD) in these models yielded additional steady states, it did not result in any significant changes to the profile in regards to cortisol levels. Combining the actions of HPA, HPG and immune regulation supported the existence of a stable hypercortisolic state in all models of men and women while a persistent hypocortisolic state was available only in women and only under certain modes of HPG regulation. Once again, while the inclusion of the GR-GRD receptor dimerization in this overarching model yielded additional steady states, it did not result in any significant changes to the homeostatic profiles.

These findings suggest that abnormally high levels of cortisol and adaptive immune activation, in this case Th1, may be perpetuated under certain conditions by the system’s own homeostatic drive. This prediction of persistent and stable Th1 activation is consistent with evidence of anomalies in immune signaling in GWI [48][65][66]. Skowera et al. measured intracellular production of cytokines in peripheral blood and found ongoing Th1-type immune activation in symptomatic Gulf War Veterans compared to healthy counterparts [65]. More recent work confirmed this finding while also suggesting that this may occur in the more complex context of a mixed Th1:Th2 response [48], something not captured by the simple immune model used here. Though we were unable to find documented reports of lower testosterone levels in GWI beyond the experimental data presented here, a large study of gulf war veterans in the UK found increased risk of fertility problems in this population [67], suggesting a possible relation.

In much the same way, conditions involving hypocortisolism and a Th2 shift may also be perpetuated at least in part by the natural homeostatic regulatory programming. In this case the homeostatic program may be driven by sex steroid suppression of the HPA axis and promotion of HPG function coupled with the mutual inhibition between the Th1 response and function of the gonadal axis, a configuration seemingly available only to female subjects in our models. This would suggest that the hypocortisolism seen in diseases, such as CFS [68][70], could be a result of the complexity afforded by the interaction between the HPA, immune and HPG axes in female subjects. Indeed model predictions describing such an alternate homeostatic state in women aligned with our experimental results from CFS subjects, and is consistent with previous findings of Th2 activation in CFS [55][71][73]. This alignment with a naturally occurring homeostatic conditions may explain, at least in part, the biased prevalence of such persistent diseases in women [74][79]. Indeed, these authors report that approximately 70% of observed CFS patients are women. Additionally, the prevalence of CFS in the 40–49-year-old age range [79], and the higher prevalence of gynecological conditions and gynecological surgeries in women with CFS [80] supports the evidence that HPA suppression by estradiol appears more likely in perimenopausal, menopausal or ovariectomized women [63][64]. Interestingly, as many as 1 in 3 CFS subjects have reported symptom relief during pregnancy [81]. The normal trend in pregnancy towards increased cortisol levels, especially in the third trimester, might be a contributing factor that would support the key involvement of sex hormone regulation proposed by our analysis [82]. While, in normal pregnancy this increase in cortisol typically coincides with an increase in cortisol-binding globulin (CBG) maintaining the level of free cortisol, CBG genetic variants in CFS have the potential to alter normal CBG function [83][84].

While certainly more comprehensive than their predecessors, these models remain relatively coarse representations of the interplay between the endocrine and immune systems.

This is particularly true of immune model granularity, especially when one considers the complex signaling network supported by immune cells as well as other immune-sensitive cells [85]. The important role of key neurotransmitters linking the central nervous system with the HPA axis and the immune system was also under-represented in this first generation of models. For example, norepinephrine and epinephrine stimulate the β2-adrenoreceptor-cAMP-protein kinase A pathway inhibiting the production of Th1/proinflammatory cytokines and stimulating the production of Th2/anti-inflammatory cytokines causing a selective shift from cellular to humoral immunity [86][87]. Additionally, lymphocytes express most of the cholinergic components found in the nervous system. Lymphocytes may be stimulated by, or release, acetylcholine thus constituting an immune regulating cholinergic system secondary to the nervous system [88]. Another neurotransmitter, neuropeptide Y (NPY), also serves as a powerful immune modulator [89] and has recently been shown to play a role in CFS [90]. These components are without question important, however based on our initial observations from this piecewise analysis we expect that increased detail will lead to the emergence of additional response programs rather than the elimination of attractors found here.

As these models are based on currently documented knowledge of human physiology and regulatory biochemistry they are necessarily incomplete. Nonetheless the simple models presented here illustrate the importance of an integrative approach to understanding complex illnesses. Further refinement of the model to include more detailed description of interactions within and between the HPA, HPG and immune systems could extend its applicability to other illnesses as would the incorporation of other key systems such as the brain and central nervous systems. Yet, even with the coarse-grained co-regulation networks investigated we found numerous stable resting states that differ significantly from normal and were indicative of complex and persistent regulatory imbalances. Findings such as this support the use of an alternate model for disease, one which is not necessarily associated with failure of individual components, but rather with a shift in their coordinated actions away from normal regulatory behavior. Response to exercise and other stressors has the potential to be very different in these new regulatory regimes. This is something that we have observed firsthand in our work with human GWI and CFS subjects [91].

Finally, when considering alignment with the experimental data presented here for CFS and GWI, it is important to remember that it was never our hypothesis that these illnesses resulted solely from the actions of homeostatic drive. Instead we proposed that homeostatic drive might be a significant contributor to the persistence of illness mechanisms. Because these naturally occurring regimes, once instantiated, provide an alternate stable homeostasis resistant to change, it may offer fertile ground in support of many chronic pathological processes. The alignment of several immune and endocrine markers modeled here with experimental data from CFS and GWI, two chronic conditions, would support at least partial involvement of the body’s own homeostatic drive in facilitating the perpetuation of these conditions. Correlation between these illness conditions and predicted stable states does not imply causation. These results do not suggest that homeostatic drive is the root cause of GWI or CFS, only that it might serve to sustain these chronic illnesses. This may promote resistance to therapy and the natural regulatory barrier to change, even positive change, should at least be considered in the design of robust treatment avenues. Knowledge of the basins of attraction identified by the modeling methods presented here can provide a comprehensive overview of multisystem dysregulation. This knowledge may be used to identify multiple therapeutic targets to be treated in conjunction to correct overall system imbalance. This opens the possibility of discrete interventions targeting multiple systems where treatment could eventually be discontinued, leaving normal regulatory drive to return the system to the correct resting state. This is very different from conventional long-term administration of a drug regimen, whereby the system is held artificially in a more desirable, but unstable state through continued intervention.

Acknowledgments

This research was conducted in collaboration with Dr. Joel Zysman, Director of High Performance Computing, using the Pegasus platform at the University of Miami Center for Computational Science (CCS) (http://ccs.miami.edu). This research was also enabled by the use of computing resources provided by WestGrid and Compute/Calcul Canada.

Author Contributions

Conceived and designed the experiments: TJAC DBM GB. Performed the experiments: TJAC PF MAR RMDR GB. Analyzed the data: TJAC PF DBM GB. Contributed reagents/materials/analysis tools: MAF NGK. Wrote the paper: TJAC DBM GB.

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Citation: Craddock TJA, Fritsch P, Rice MA Jr, del Rosario RM, Miller DB, Fletcher MA, et al. (2014) A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome. PLoS ONE 9(1): e84839. https://doi.org/10.1371/journal.pone.0084839

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ME/CFS: A natural history

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HYPOTHESIS AND THEORY ARTICLE

Front. Neurol., 11 August 2020 | https://doi.org/10.3389/fneur.2020.00826

How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS

Luis Nacul1,2Shennae O’Boyle1*Luigi Palla3,4Flavio E. Nacul5Kathleen Mudie1Caroline C. Kingdon1Jacqueline M. Cliff6Taane G. Clark6Hazel M. Dockrell6 and Eliana M. Lacerda1

  • 1Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
  • 2B.C. Women’s Hospital and Health Centre, Vancouver, BC, Canada
  • 3Department of Medical Statistics, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
  • 4Department of Global Health, School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
  • 5Pro-Cardiaco Hospital and Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
  • 6Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom

Originally publication:

Nacul, L., O’Boyle, S., Palla, L., Nacul, F. E., Mudie, K., Kingdon, C. C., … & Lacerda, E. M. (2020). How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS. Frontiers in neurology11, 826.

Abstract

We propose a framework for understanding and interpreting the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that considers wider determinants of health and long-term temporal variation in pathophysiological features and disease phenotype throughout the natural history of the disease. As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease. Disease incidence depends on genetic makeup and environment factors, the exposure to singular or repeated insults, and the nature of the host response. In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states. Thus, the predominantly neuro-immune manifestations, underlined by a hyper-metabolic state, that characterize early disease, may be followed by various processes leading to multi-systemic abnormalities and related symptoms. This abnormal state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production. These processes do not seem to happen uniformly; although a spiraling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium. With time variation in disease presentation, no single ME/CFS case description, set of diagnostic criteria, or molecular feature is currently representative of all patients at different disease stages. While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may support future research design and health care interventions for people with ME/CFS.

Introduction

The lack of progress in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) research has been attributed to a range of factors, including the paucity of large, high quality, hypothesis-driven studies, and controversy around diagnosis. Without recognized and validated biomarkers or diagnostic tests, there is an over-reliance on patient history for diagnosis, which is based on criteria with limited sensitivity and specificity (1) and which ignore disease sub-groups. Furthermore, the lack of consistency in the choice and application of research case definition has led to problems with reliability and comparability of research findings (2). An additional factor complicating diagnosis and case definition for research studies is the time-related variation in phenotype both in the short- (34) and long-term (5), which has seldom been considered in research studies.

In addition to often marked variability in disease presentation, severity, progression, and duration among different individuals, the way disease manifests in each individual may change with time. Inter- and intra-individual phenotypic variations lend toward the categorization of different subtype trajectories of ME/CFS that may differ in pathogenesis and prognosis. In some studies, female sex, increased age (68), and lower socio-economic status (9) have been found to predict poor prognosis; however, the variable nature of both population sampling and diagnostic criteria has led to ambiguous results and has reinforced the need for ongoing research in this area (10). Further subtypes have been defined on the basis of “minor” symptoms i.e., musculoskeletal, infectious, or neurological (11), through genetic studies (1213), metabolomics studies (14), and, duration of disease studies (5), highlighting the multitude of possible ways ME/CFS patients can be categorized. Other studies have identified variations in symptom profiles as disease progresses; however, such results are often limited by cross-sectional study design (15), and/or recall bias (16). The breadth of subtype studies available follow a similar model of looking for patterns across patient groups at single time-points; far fewer consider longitudinal subtyping and disease progression of a single patient cohort over time.

The concept of the natural history of disease is well-understood in public health and medicine: many, if not all, diseases are framed using this construct to formulate how they progress from a pre-illness stage to a final disease outcome, which may vary from full recovery to death. A good understanding of the disease course is vital not only for the design of preventative and intervention studies (17), but also to assess the timing and type of intervention that minimizes disease risk or optimizes prognosis. Although there is some understanding of the natural history of ME/CFS, this has been limited by problems in case definition (as above) as well as by the paucity of longitudinal studies, and in particular those that follow up individuals’ pre-illness. A review of studies on CFS prognosis (8) suggested recovery rates under 10% in adults, and an improvement rate over 40% for people with fatigue lasting <6 months. The prognosis was worse: when more stringent case definitions were used; in older people; in cases with more severe symptoms; and, in the presence of psychiatric co-morbidity. A subsequent systematic review on prognosis found a median recovery rate of 5%, and median proportion of people improving of 39.5% (18) with most reporting symptoms still present at follow-up.

This conceptual paper explores the long-term course of ME/CFS and how presentation and pathophysiological abnormalities may vary with time. The pathophysiological concepts discussed are based on evidence from clinical observations and research, where available, and, as such, are not claimed to be original or indeed conclusive. Instead, they serve to highlight our proposed characterization of ME/CFS’s distinct stages within the framework of the natural history of the disease.

Pathophysiological and Cellular Abnormalities Following Host Exposure to “Insults” or “Stressors”

Prior to exploring the course of ME/CFS, we propose to revisit some concepts related to mechanisms of disease that have been used in the context of life-threatening emergencies and to potential return to homeostasis, such as those occurring in sepsis or poly-trauma. Although very different to ME/CFS, these acute injuries have been extensively studied, and the high intensity and speed of events result in changes that are easily identified and well-described, from potential homeostatic failure to recovery. We present the following models as a paradigm for the understanding of disease mechanisms, based on well-studied examples. They merely serve as a reference for mechanisms that the host may partially engage with in the presence of insults of different severities. Hence, in the following paragraphs, we explore the pathophysiological mechanisms that may be taking place in ME/CFS, which have been related to abnormal homeostasis guided by these established disease descriptions.

The response to an insult frequently involves multiple body-systems and has components that are independent of the etiology of the insult and, to some extent, its severity. There are many commonalities between the response to sepsis and to poly-trauma: both are acute and severe insults, to which many of the aspects of the host response are indistinguishable. Our proposal is based on the idea that there may be some similar mechanisms at play when individuals predisposed to ME/CFS are faced with a range of “insults” or “stressors.” Needless to say, the hyper-acute changes and co-factors in both sepsis and poly-trauma occur in very rapid sequence, whereas in ME/CFS, physiological changes, even if they resemble those of acute injury in some respects, take place at a much slower pace with less obvious and uniform patterns.

Non-specific Changes in Response to Severe Acute Injury

In both sepsis (19) and poly-trauma, (2021) a state of hyper-inflammation is observed initially as the host responds to the infection or traumatic stress with marked production of pro-inflammatory mediators, e.g., cytokines and polypeptides. A failing circulatory system is associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and increased sympathetic drive, contributing to metabolic changes and to increased energy expenditure (2223).

In these conditions, the acute pro-inflammatory state is usually followed by a compensatory anti-inflammatory response, with a different profile of biochemical and molecular mediators. The success of the host in balancing pro- with anti- inflammatory responses alongside injury-related factors, are key to improved long-term outcomes. The direct and indirect effects of immune cells and active products derived from immune, neural, and endocrine systems (some of which cause pathology if present in excess) contribute to a number of physiological changes, including those leading to the formation of reactive oxygen species (ROS, oxidative stress) and reactive nitrogen species (RNS, nitrosative stress). Endothelial and parenchymal (organ) cell damage may result because of a combination of factors, such as polymorphonuclear leukocyte infiltration and the action of reactive oxygen and nitrogen species, cytokines, vasoactive amines, and other products. Endothelial dysfunction results in capillary leakage, accelerated inflammation, platelet aggregation, coagulation, and loss of vascular tone (24). Vascular dysfunction is associated to peripheral vasodilation due to increased nitric oxide and prostacyclin synthesis (25) and to a decrease in the proportion of perfused vessels and an increase in the heterogeneity of blood flow distribution (26). This results in relative hypovolemia, decreased capillary flow, haemo-concentration, and micro-thrombi formation, and further contributes to reduced exchanges of oxygen and nutrients at the microcirculatory level. The consequent decreased cellular oxygen delivery eventually leads to cytopathic hypoxia. Adenosine triphosphate (ATP) increased consumption and ensuing deficits cascade into a range of metabolic disturbances with systemic effects (27), and promote changes in membrane permeability that lead to dysfunctional transmembrane ion transport. In acutely and severely ill patients, reperfusion results in further oxidative damage (2228). Additional failures of biological and cell processes lead to multiple dysfunction, to system and organ failure, and to potentially irreversible disease (22).

Evidence of Abnormalities in ME/CFS and Loss of Normal Homeostasis

Concepts that are relevant here are those of homeostasis and allostasis. While homeostasis refers to the “stability of physiological systems,” allostasis has been defined as “the adaptive processes aimed to maintain homeostasis following acute stress, and which contribute to wear and tear on the body and the brain, or allostatic overload” (29). A central characteristic of individuals with ME/CFS points to a state of homeostatic failure (30), aggravated by the incidence of, or increase in, levels of new stressors or by the increase in allostatic load (31). Typical stressors include infection [(32): 17–21], physical exertion and cognitive effort (e.g., reading or solving mental puzzles) triggering post-exertional malaise (PEM) (33), comorbid conditions (e.g., sleep disturbances) (34) and a range of environmental and individual factors (3540).

In those who do not develop ME/CFS or prolonged illness following an insult such as an acute infection, external stressors may initially cause physiological changes accompanied by non-specific symptoms, but the state of homeostatic equilibrium that operated before the insult is quickly restored. Failing re-establishment of this equilibrium, there may be a shift to a state of “aberrant homeostasis,” where physiological processes converge to a new or alternative state of functioning; a state that remains homeostatic in nature, but functions at a less optimum level (41). While such a state may be adequate for many physiological processes, it will be inadequate or inefficient for a number of other processes and functions and the prolongation of such aberrant functioning will represent another potential source of ongoing stress.

There is a growing body of evidence on biological abnormalities in ME/CFS that has been reviewed elsewhere (324243), and summarized by Komaroff (44). Of note, many of the abnormalities shown in severe injury have also been identified in ME/CFS such as: immune dysfunction, including pro-inflammatory response (especially at early stages of disease) (4546); autonomic nervous system (4749); HPA axis dysfunction (50); hypovolemia (51); nitrosamine and oxidative stress (52); endothelial dysfunction (52); metabolic dysfunction (5355); dysfunction of membrane transport (56); and, tissue hypoxia (57).

The Stages of ME/CFS

Other tools widely used in clinical medicine are staging systems. Using sepsis again as an example, such a system was proposed at the International Sepsis Definitions Conference in 2001 to introduce the stratification of patients with sepsis (58). By applying PIRO (predisposition, infection/insult, response, and organ dysfunction) patients are stratified into appropriate subgroups allowing for more accurate prognostication in emergency medical services (59). The idea of classifying people with ME or CFS into distinct categories or stages has been explored previously by several theorists. One school of thought proposes categories based on the psychological process of coming to terms with this new and evolving state of health rather than addressing biological differences, and are defined as such by the emotions common to any trauma experience: e.g., denial, fear, frustration, and acceptance (6061). Alternatively, Schweitzer (62) proposes the different presentations of CFS according to more physical categories (Prodrome, Relapse and Remission, Improvement and Plateau, and Collapse followed by slow worsening with no remission); it is these that we aim to expand on, as follows.

We show a tentative representation of the key pathophysiological mechanisms operating in each stage of ME/CFS in Figure 1. As in severe injury or sepsis, the range and order of occurrence of biological processes taking place in ME/CFS may vary, as may their relative significance and impact on each individual. Therefore, it is important to note that although the various abnormalities may occur continuously and often simultaneously, the predominance of specific dysfunctions varies over time and from individual to individual.FIGURE 1

Figure 1. Hypothesized key pathophysiological mechanisms for ME/CFS.

Furthermore, we propose a characterization of disease stages in ME/CFS, based on the natural history of disease framework considering available descriptions from the literature (32), and the life-stories reported by our own cohort of research participants with ME/CFS (including those with mild/moderate or severe symptoms) (63). This characterization is summarized in Table 1, which may be used in support of research designs that consider the disease presentation in distinct phases.TABLE 1

Table 1. Proposed characterization of disease stages in an individual with ME/CFS, within the framework of natural history of diseases.

Predisposition and Triggering of Disease

Individuals with a combination of genetic predispositions and exposures to environmental factors may first manifest symptoms of ME/CFS following their encounter with a specific trigger, of which acute infections of various etiologies are the most commonly reported (6465); other patients report a more insidious onset with no obvious initiating factor (32). While it remains unclear exactly which individuals are predisposed to develop ME/CFS and why, some patterns have emerged. For example, gender- and age-specific factors are thought to contribute to the risk of ME/CFS (66), with epidemiological studies consistently reporting higher rates of the disease in females (6768). Although most cases are endemic, there have been reports of epidemic cases, suggesting an infectious or other environmental cause play a role (436972); although discrepancies in onset patterns and case definitions make these epidemics difficult to compare (72). Many studies have reported an association between acute viral infection and the development of ME/CFS (7376). Cases are predominantly reported in North America, Europe, and Oceania; however, the occurrence of ME/CFS is thought to be global with evidence of cases in other parts of the world (7779).

Psychiatric morbidity, experiences of stress and trauma, either physical or emotional have been reported to precipitate the disease (168082) and to predict disease progression (83), under the explanatory biopsychosocial models. However, these models have not been replicated (8485). Furthermore, Chu et al. (16) found that even when a significant proportion of their research population report stress or a major life event as a precipitating factor for ME/CFS, “stressful events were rarely chosen as the only precipitant though, endorsed only by 8% of our subjects, and appeared mostly in conjunction with infection or other precipitants.” We acknowledge that stress may play a role in the development and perpetuation of ME/CFS through its role on the immune system and HPA axis dysfunction (86), or by aiding transmission or reactivation of viral infections (87), or as a consequence of the loss of normal functioning experienced by the individual.

The role of genetic variation has been supported by a number of family-based studies assessing the possibility of a heritable component (8890). Genes underpinning immune system function and inflammatory response may contribute to genetic susceptibility for ME/CFS; some studies suggest associations with human leucocyte antigen class II alleles (9192) and in genes related to the complement cascade, chemokines, cytokine signaling, and toll-like receptor signaling (93). Small genome-wide association studies (GWAS) have had little overlap in results save for two SNPs in the GRIK2 gene: a gene implicated in a number of neurological conditions such as autism and schizophrenia (98); in the GRIK3 gene: relating to a pattern recognition receptor capable of binding to a broad range of pathogens; and in the non-coding regions of T-cell receptor loci (99). A further study reported SNP markers in candidate genes involved in HPA axis function and neurotransmitter systems that distinguished individuals with ME/CFS (100).

Prodromal Period

It is important to preface here that, with the current diagnostic methodology of ME/CFS stipulating the presence of symptoms for more than 6 months (101102) and the absence of a positive validated diagnostic test, the following processes (occurring pre-diagnosis) are difficult to substantiate from existing biomedical research. However, based on the published work on ME/CFS and considering the pathophysiological events happening in sepsis and polytrauma may be similar (though in a much slower pace), we hypothesize that the following may occur.

In addition to any manifestations specifically related to the acute insult or triggering event, the mechanisms involved in producing the first symptoms of ME/CFS may be similar to what has been described in relation to “sickness behavior” (103) or in those with severe acute disease, i.e., “systemic inflammatory response syndrome” (19). These result from the interaction of an infective agent or other insult with the host’s immune system, as well as their potential effect on the host’s central nervous system (CNS). The immune system-nervous system interactions involve bidirectional signals (104106): while immune system activity may interfere with CNS function via various mechanisms, e.g., release and action of pro-inflammatory cytokines and other mediators, various neurotransmitters, neuropeptides, and neuro-hormones may also affect immune function. Additionally, the HPA system and the autonomic nervous system (ANS) are affected, with consequences that may be observed well-beyond the CNS. These effects may vary according to different factors, such as host susceptibility, the nature and persistence (or return to normality) of systemic and local immune dysfunction, altered CNS metabolism, neuro-transmission, brain perfusion changes, and the integrity of the blood-brain barrier (107110).

Particular characteristics of the specific infectious agent or stressor may also play a role during this prodromal stage, which would explain the different risks of disease development following acute infection. For example, there has long been an interest in the association between ME/CFS and infections such as Epstein-Barr virus (EBV) and other herpesviruses (73111116). Herpesviruses tend to be neurotropic and persist following acute infection in a latent state. Similar to EBV infection (117), the risk of chronic fatigue has been shown to be substantially increased following viral meningitis, a relatively severe infection of the CNS (83).

Early Disease

Early disease represents a continuation of the processes initiated at the prodromal period, when there is a failure of physiological and homeostatic processes to resume previous levels of equilibrium and normality. Fatigue and other symptoms may be largely explained by a combination of the local and systemic effects of pro-inflammatory and other mediators or toxins, CNS metabolic dysfunction (with enhanced excitability and other changes), and a systemic hyper-metabolic state. With higher energy demands for essential biological processes, there will be a reduction in the available energy for less essential tasks, including those demanding increased physical or mental exertion. The increased production and action of anti-inflammatory mediators, as well as their ability to counter-balance pro-inflammatory stimuli, modulate physiological responses, and symptoms and affect disease progression or reversibility. As mentioned previously, without a validated biomarker to diagnose ME/CFS early it is difficult to substantiate the exact mechanisms occurring in the early disease phase. Research into potential diagnostic markers, such as the recent study on impedance signatures (118), are crucial not only clinically, but to identify these mechanisms as possible targets for early intervention.

Established ME/CFS

The persistence of immune and CNS dysfunction with the initial over-production of pro-inflammatory and neurotoxic factors may result in a prolonged state of low-grade neurological and systemic inflammation. In the CNS, a status of glial activation with microglial hypersensitivity to peripheral (119) and regional stimuli is established (104119121), akin to what has been described in chronic pain states (122). In support of CNS dysfunction, neuroimaging studies have shown various abnormalities in ME/CFS, often associated with symptoms of fatigue and other indications of severity (123). Glial activation in several areas of the brain has also been demonstrated in positron emission tomography (PET) scans of patients with fibromyalgia (FM), compared to controls, which was correlated to the severity of fatigue (123124). Neuro-glial bidirectional signaling is associated with increased production of neuro-excitatory neurotransmitters and immune-inflammatory mediators (120).

Nervous system dysfunction affecting parts of the brain, brain stem, and ANS, could explain not only the encephalopathic or neuro-cognitive type of symptoms, but also those resulting from disruption of key central regulatory mechanisms, such as those involved in endocrine, circulatory, thermoregulation, and respiratory control (163248120125). Examples of these include intolerance to extremes of temperature, chills and temperature variations, intolerance to exertion, hyperventilation or irregular breathing, orthostatic intolerance, with hypotension or postural orthostatic tachycardia, and other symptoms related to autonomic and endocrine control function (102).

Among the various by-products produced as a consequence of ongoing abnormalities, are highly ROS and nitric oxide synthase (NOS) or free radicals, which affect cell signaling and cell functioning and structure, particularly when present at high levels. It has been hypothesized that free radicals, and increased levels of nitric oxide and peroxynitrite in particular, play a significant role in ME/CFS (126127); their links to immune and neuro signaling, cell integrity, mitochondrial function, and energy metabolism may play an important part in the long term abnormalities in ME/CFS.

The nature of neuro-immune and other dysfunctions may change as disease progresses. While a pro-inflammatory state is typical of the early response to insults, immune abnormalities may become less marked (and less pro-inflammatory) with time (128), and patients with longer periods of illness may show fewer inflammatory immunological abnormalities. In support of this, our preliminary results from the analysis of over 200 ME/CFS patients participating in the UK ME/CFS Biobank (UKMEB), showed that the reported time since disease onset was significantly associated with 2 cytokines, namely SCD40L and IL1RA (manuscript in preparation). These results were found after aliquots of peripheral blood mononuclear cells (PBMC) from participants were stimulated (i.e., subjected to an infection resembling stimulus) and analyzed with MAGPIX® multiplexing system. The statistical analyses were conducted after transforming each cytokine measurement to the logarithm scale to approximate normality; linear regression of these log-transformed values (adapted for truncated outcome variables to account for the assay’s limits of detections) was applied to the variables’ time since onset, level of severity (mild to moderate vs. severe) and the interaction between severity and time since onset, while also adjusting for age and sex. The results evidenced a decrease of sCD40L—a pro-inflammatory cytokine—and an increase of IL1RA—an anti-inflammatory cytokine—for every additional year since onset of ME.

Long-Term, Advanced, and Complicated Disease

As the disease progresses, physiological, and systems abnormalities take their toll and cell dysfunction becomes more pronounced. Endothelial dysfunction may arise as a consequence of a range of factors, including, but not limited to, persistent oxidative and nitrosative stress and circulatory dysfunction (4352126129130). The associated reduced delivery of oxygen and nutrients to the cell leads to a deterioration of cell function and impaired energy metabolism (129131132) and a decreased ability of the cell to extract oxygen and produce energy, a condition known as cytopathic hypoxia. As suggested by Naviaux et al. (54), in cases of ME/CFS with mean duration of symptoms over 17 years, there is a shutting down of various metabolic processes leading to a hypometabolic state, i.e., a move to an energy-saving mode. At this stage, symptoms are likely to be severe, with profound fatigue, intolerance to effort, PEM and other systemic symptoms, which are largely explained by the slowness of physiological and metabolic processes and decreased energy production.

Discussion

Disease Severity and Reversibility

It is unknown how the initial host response to a stressor or insult compares in individuals who do or do not develop typical symptoms of ME/CFS. However, the return to good health, which happens to most people following exposure to mild or moderate levels of insult, seems to be impeded in ME/CFS when symptoms persist for longer than 3–6 months; the time interval that is featured in some of the currently used diagnostic criteria (2101102). This suggests that subsequent mechanisms involved in the host response will differ at some point in those who develop ME/CFS from those who regain full health. Therefore, a key question is what determines full recovery? Or alternatively, what determines the perpetuation and transformation of symptoms?

While the abnormalities observed in acute disease are general and mostly reversible once the challenge from the stressor ceases, some degree of dysfunction may persist for longer periods. The degree of reversibility of various physiological abnormalities is likely to decrease with time, and some permanent functional, and even structural, damage may occur consequently. This is likely caused by either the persistence or frequent reactivation of the initial stressor (87133), an accumulation of insults, a continuing dysfunctional host-response, or the effects of the numerous psychosocial risk factors that influence disease development and progression (134), or a combination of all of these.

Although our framework focuses on the underlying biological mechanisms that may be at play in the development and progression of ME/CFS, it is important to acknowledge the impact of psychosocial and behavioral aspects in the progression of chronic diseases. Stressors such as stressful life events, low satisfaction with social and medical support, and excessive use of coping mechanisms, have been shown to contribute to the neuroendocrine and immune responses by acting through complex pathways that ultimately affect health and health outcomes (134136).

The interplay between these three dimensions (biological, psychosocial, and behavior) has been noted in the development and the progression of a number of chronic diseases and to influence disease outcomes (136139). The combined effects of stress from work or family life, social deprivation, and depression have been found to contribute to the risk of cardiovascular diseases, including coronary heart disease (140) and myocardial infarction (141), and to a worse prognosis (142) by enhancing cortisol secretion, increasing sympathetic activation, and elevating plasma catecholamine levels (143). A higher cumulative average number of stressful life events, when coping involves denial, and higher levels of serum cortisol have been found to be associated with a faster progression to AIDS (144). Correspondingly, low stress levels and low scores of avoidance coping behaviors were shown to be protective against relapse in Crohn’s disease patients (135) in contrast to high levels, which act as mediators, overloading the sympathetic nervous system.

In the case of ME/CFS, the effect of these dimensions is the same. In fact, one framework has been used to propose a model for managing patients with this disease in which it is considered that genes predispose, life events precipitate, and behaviors perpetuate (145147). However, this model may downplay the important role of the biological mechanisms involved in ME/CFS and overstate the role of psychosocial and behavioral factors (148).

The pathophysiological distinction between cases from the milder to the more severe end of the ME/CFS spectrum may relate to near-normal homeostatic regulation in milder cases, and established “aberrant homeostasis” or homeostatic dysregulation with multi-systemic consequences in moderate to severe cases. Alternatively, homeostatic failure, along with variable multi-system physiological failure and increasing degrees of irreversibility, may happen in the most severe cases.

The early stage of ME/CFS is of variable duration but is usually considered to be between 4 and 6 months to 2 years after the start of prodromal symptoms. Reversibility is possible, but often people will evolve to chronicity or established ME/CFS with either: (a) partial reversal of dysfunctional physiological mechanisms (mild cases with slow improvement over time); (b) persistence of dysfunctions and symptoms (mild or moderate cases with stable symptoms or slow changes over time); or (c) worsening dysfunctions and symptoms (moderate and severe cases) (149). Note that some cases present early with severe symptoms, which not uncommonly evolve to a milder form (150). The use of coping mechanisms, such as pacing, can also help improve energy management in people with ME/CFS over time and reduce the risk of relapse into a more severe state; however, there is little evidence that these will lead to a reversibility (151). There is some indication that rates of resolution are higher in cases of epidemic CFS compared to sporadic cases, although very few of these individuals will recover to their pre-morbid level (152).

One way of thinking about these phases is as interconnected spirals, each representing a distinct disease phase. Individuals may either remain for long periods in a single phase with symptoms fluctuating within the “spiral section” or move between phases either upwards (i.e., toward better health status) or downwards (i.e., toward disease deterioration). Figure 2 represents an illustration of the multi-spiraling disease course suggested for ME/CFS, and shows how patients may move across spirals, with different molecular and system abnormalities.FIGURE 2

Figure 2. Hypothetical stages of disease in ME/CFS.

Common Comorbidities in ME/CFS

There are a number of comorbid conditions associated with ME/CFS and, as such, these comorbidities can complicate diagnosis, treatment and research of the disease. Comorbidities have been found in up to 97% of people with ME/CFS (PWME) (16153) with some developing before, with, or after ME/CFS onset (102). The complexity of ME/CFS is in part due to the number of different systems affected that contribute to the many and varied symptoms experienced. ME/CFS and FM share a number of overlapping core symptoms that mean the two are commonly experienced together; FM has been reported to co-occur in 12–91% of PWME (16154155). However, there is evidence to suggest the two conditions differ in their hormone dynamics, genetic/molecular biology, and autonomic function (156157). This is reiterated by the absence of post-exertional malaise in FM (158159), which is one of the key features of ME/CFS (2101102160).

Sleep disturbances can cause some symptoms that are also present in ME/CFS including fatigue, joint pain, and impaired cognition (161165). Additionally, as part of a bidirectional relationship, comorbid pain conditions may further impact sleep quality (34). Sleep disturbances are also present in a number of neurological diseases (166), which would explain their presence as an important feature in ME/CFS (2160); however, differences in sleep cycle patterns and distinct sleep phenotypes suggest that ME/CFS and primary sleep disorders are, in fact, different entities (167168) with many PWME showing normal sleep study results (169). Primary sleep disturbances are considered exclusionary for ME/CFS by a number of diagnostic criteria (101102160), however, with little evidence that treatment of these disorders improves symptoms of ME/CFS it is argued they are better considered as comorbid conditions (234170).

Also highly prevalent in those with ME/CFS is orthostatic intolerance (OI), a common multifactorial disorder commonly accompanying neurodegenerative, cardiovascular, metabolic, and renal disorders (171). Disruptions to ANS and reduced blood volume contribute to OI (172) and the same systemic dysfunctions have been reported in those with ME/CFS (51); however, not all people with OI disorders have ME/CFS (173174).

Intestinal dysbiosis thought to be associated with some CNS-related disorders via the gut-brain-axis (175). IBS is another largely overlapping syndrome with both ME/CFS and FM but metabolic profiles are distinct in ME/CFS and ME/CFS with IBS subgroups (176). Some authors hypothesize IBS could be considered an initial symptom of ME/CFS, as they reported that 65% of IBS patients followed up developed ME (177). Authors of a co-twin control study found significant associations between CFS and FM, IBS, chronic pelvic pain, multiple chemical sensitivities, and temporomandibular disorder. After controlling for psychiatric risk factors, they argued that these associations could not be attributed to uniquely psychiatric illness, thus suggesting a “complex interplay of genes and environmental factors” to help explain the clinical picture (178).

While healthcare costs likely increase following the diagnosis of additional comorbidities (178), treating comorbidities may improve the quality of life of PWME (2) not only symptomatically but also in what they might be able to contribute to the economy. We argue that by using the proposed natural history framework, how and when common comorbidities develop in relation to ME/CFS may be highlighted, allowing researchers, and clinicians to better tailor potential interventions according to each phase, thus resulting in a more efficient management of costs.

Research Implications

These distinct hypothetical stages may help explain the apparent inconsistency of findings from ME/CFS studies, which likely include cases at distinct stages of disease with potentially diverse systems abnormalities. Hence, we consider that the conceptual approach presented in this paper may help to elucidate pathophysiological mechanisms that may be more prominent at different stages of disease; and consequently, could indicate potential target therapeutic approaches in future. We argue that the different stages patients go through during the course of the disease, their severity, and the presence and degree of complications are key parameters for disease stratification.

Research leading to an understanding of what is occurring during the first three stages of progression to ME/CFS is greatly needed but requires the recruitment of individuals for research at pre-illness stage. Such research could be invaluable to understanding the biological mechanisms at play before, during and after an insult, and research using proxy disease models for ME/CFS (85) or follow up of patients after an acute viral infection [e.g., mononucleosis (76) or more presently COVID-19] could begin to address this knowledge gap. Electronic health records could also be a valuable source of retrospective pre-illness data in people with ME/CFS. Well-designed longitudinal studies, with strict protocols, would help refine this attempted description of the natural course of the ME/CFS, and the interpretation of the findings.

Conclusions

The concept of the natural history of disease, common in the field of public health and medicine, serves to frame a disease according to how it progresses from a pre-illness stage to the final disease outcome. Due to the lack of knowledge surrounding the etiology of ME/CFS, the heterogeneous presentation of symptoms and their severity, and the lack of a recognized and validated biomarker to determine diagnosis, the natural history of this disease has been hard to determine. While current research efforts tend to group ME/CFS subtypes according to clusters of symptoms, few studies have considered ME/CFS as a continuum.

Pathophysiological patterns and changes along and across disease stages result in the expression of different, albeit overlapping phenotypes as seen in the preliminary UKMEB findings related to changes in cytokine levels and symptoms scores with time of disease, reported here. Ignoring phenotype temporal variation in ME/CFS may have an impact on the outputs and the interpretation of research investigating disease mechanisms, pathways, and interventions.

This paper sought to provide a simple framework, similar to those of other chronic diseases, in an effort to extend the temporal perception of ME/CFS and better incorporate the less defined pre-illness stages of the disease. We believe that by applying this framework to ME/CFS research efforts could better elucidate the pathophysiological mechanisms of the disease and identify potential therapeutic targets at distinct stages.

Data Availability Statement

The datasets generated for this study are available on request to the corresponding author.

Ethics Statement

Ethical approval was granted by the LSHTM Ethics Committee 16 January 2012 (Ref.6123) and the National Research Ethics Service (NRES) London-Bloomsbury Research Ethics Committee 22 December 2011 (REC ref.11/10/1760, IRAS ID: 77765). All biobank participants provided written consent for questionnaire, clinical measurement and laboratory test data, and samples to be made available for ethically approved research, after receiving an extensive information sheet and consent form, which includes an option to withdraw from the study at any time and without any restrictions.

Author Contributions

LN and EL conceived the paper. LP and EL provided the preliminary findings from data from the UKMEB participants and possible interpretation of them. SO’B contributed to drafting, referencing, and formatting. All authors contributed to drafting and to revising the manuscript and approved the final version to be published.

Funding

The UK ME/CFS Biobank was established with a joint grant from the charities ME Association (including continuing support), ME Research UK and Action for ME, as well as private donors. Research reported in this manuscript was supported by the National Institutes of Health under award number 2R01AI103629. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Chronic Fatigue Syndrome, ME/CFS, chronic illness, management, research

Citation: Nacul L, O’Boyle S, Palla L, Nacul FE, Mudie K, Kingdon CC, Cliff JM, Clark TG, Dockrell HM and Lacerda EM (2020) How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS. Front. Neurol. 11:826. doi: 10.3389/fneur.2020.00826

Received: 18 December 2019; Accepted: 01 July 2020;
Published: 11 August 2020.

Edited by:Bernhard Schaller, University of Zurich, Switzerland

Reviewed by:Indre Bileviciute-Ljungar, Karolinska Institutet (KI), Sweden
Lucinda Bateman, Bateman Horne Center, United States

Copyright © 2020 Nacul, O’Boyle, Palla, Nacul, Mudie, Kingdon, Cliff, Clark, Dockrell and Lacerda. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Shennae O’Boyle, shennae.oboyle@lshtm.ac.uk

ME/CFS: a brain MRI study

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NMR in Biomedicine

Research Article Open Access

A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis

Leighton R. Barnden Benjamin Crouch Richard Kwiatek Richard Burnet Anacleto Mernone Steve Chryssidis Garry Scroop Peter Del Fante First published: 11 May 2011 https://doi.org/10.1002/nbm.1692 Citations: 52

Abstract

To explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR images has been extended to voxel‐based regressions against clinical scores. Using SPM5 we performed voxel‐based morphometry (VBM) and analysed T1‐ and T2‐weighted spin‐echo MR signal levels in 25 CFS subjects and 25 normal controls (NC). Clinical scores included CFS fatigue duration, a score based on the 10 most common CFS symptoms, the Bell score, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24‐h blood pressure monitoring. We also performed group × hemodynamic score interaction regressions to detect locations where MR regressions were opposite for CFS and NC, thereby indicating abnormality in the CFS group. In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T1‐weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction. These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).

© 2011 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.

Abbreviations used

ANS autonomic nervous system

BBB blood‐brain barrier

BP blood pressure

CA cerebrovascular autoregulation

CAN central autonomic network

ccP corrected cluster p statistic

CFS chronic fatigue syndrome

CNS central nervous system

CSF cerebrospinal fluid ECG electrocardiograph

FDR false discovery rate

FWE family wise error FWHM full width at half maximum

GM grey matter

HADS hospital anxiety and depression scale

HPA hypothalamo‐pituitary‐adrenal

HR heart rate MNI

Montreal Neurological Institute

NC normal controls PET positron emission tomography

PP pulse pressure

ROI region of interestr

WMv relative white matter volume image

SPECT single photon emission computed tomography

SPM statistical parametric mapping

SSsymptom score

T1wT1 weighted spin‐echo

T2wT2 weighted spin‐echo

uvP uncorrected voxel P statistic

VBISvoxel‐based iterative sensitivity

VBMvoxel‐based morphometry

WMwhite matter

INTRODUCTION

Chronic fatigue syndrome (CFS) is characterized primarily by debilitating fatigue lasting at least 6 months and of new or definite onset and with no alternative medical explanation 1. Secondary symptoms include cognitive impairment 23 and symptoms consistent with autonomic nervous system (ANS) 4, immunological 57 and cardiovascular 89 dysfunction.

Although the aetiology of CFS has not been established, primary involvement of the central nervous system (CNS) has been suggested 10. On the basis of consistent post‐mortem findings of midbrain reticular formation lesions in acute poliomyelitis, which has symptoms of severe fatigue, midbrain dysfunction has been postulated as a common mechanism for all post‐viral fatigue 1112. Another CNS mechanism proposed in CFS is dysfunction of the hypothalamo–pituitary–adrenal (HPA) axis that mediates stress response. Although results from challenge tests are mixed 13 and HPA dysfunction is probably secondary to other factors 14, it may be relevant in CFS symptom propagation.

Cerebral imaging studies comparing CFS subjects with normal controls (NC) have been inconclusive. An elevated occurrence of frontal lobe MR white matter (WM) hyperintensities has been reported in some studies 1516 but not others 17. In studies using single photon emission computed tomography (SPECT) and positron emission tomography (PET), some groups have reported brainstem and prefrontal changes 1820. A PET study comparing multiple sclerosis subjects with and without fatigue also detected differences in extended prefrontal grey (GM) and WM 21. Voxel‐based image analysis of MR in CFS with statistical parametric mapping (SPM) is limited. One voxel‐based morphometry (VBM) study detected decreased grey matter volume in dorsolateral prefrontal grey matter 22, but another did not 23.

The failure to detect consistent patterns of brain involvement in CFS may be due in part to the considerable variability in the symptoms and symptom severity among CFS subjects 2425. If, in a CFS population, MR image values at a brain location vary appreciably with a clinical score, then a correlation against that score may be statistically more powerful than a CFS versus NC group comparison that would be degraded by the large variance within the CFS group. We have therefore adopted an additional approach, namely to perform voxel‐based regressions of MR image values against CFS clinical scores.

In the present study, voxel‐based regressions are utilized in two ways: first, regressions of the images from the CFS group against CFS scores to locate regions where MR changes correlate with increases in symptom severity or disease duration were performed. Second, so‐called group versus clinical score interaction regressions, that involve both CFS and NC groups to detect locations where the regression is different in the two groups, were applied. The second approach provides a powerful method to investigate locally disrupted CNS homeostasis, such as might be expected if the global control functions of the midbrain are affected in CFS. If, in the NC group, MR values correlate locally with a clinical score, then in a collective sense, this relationship is an expression of CNS homeostasis. If interaction regressions locate voxels where regressions are significantly different for the CFS and NC groups, particularly if they have opposite slopes, this will provide strong evidence of abnormality in CFS.

In the present study, MR analysis was extended beyond VBM to also assess signal levels at the voxel level in T1‐ and T2‐weighted spin‐echo (T1w and T2w) scans. This was facilitated by a recently developed method to normalize cross‐subject T1w and T2w global signal levels 26T1 and T2 relaxation times are fundamental properties of tissue. In the brain, both T1 and T2 are prolonged in tissue‐free water such as in cerebrospinal fluid (CSF) and oedema 27, but only T1 is prolonged in gliosis 28. In addition, macromolecules (in particular myelin) and membranes shorten T1 29 and locally increased regional cerebral blood volume shortens T2 30T1w is inversely proportional to T1 (so T1w decreases in oedema and increases with increasing myelination), whereas T2w is directly proportional to T2 (T2w increases in oedema and with decreased local blood volume).

Scoring CFS status is contentious. In addition to fatigue duration, we recorded the self‐reported Bell CFS disability scale 31, and the sum of scores of the 10 most common CFS symptoms 2432. To investigate reports of autonomic dysfunction in CFS 33, 24‐h ambulatory blood pressure monitoring and bedside haemodynamic stress tests were also performed. Twenty‐four‐hour haemodynamic parameters were averaged separately in asleep and awake (and seated) sub‐periods, the latter avoiding contamination by the autonomic effects of variable physical activity. To our knowledge, voxel‐based MR regressions against haemodynamic scores have not yet been performed in NC alone, so our analysis here is unique.

Our working hypothesis then was that quantitative techniques developed for automatic voxel‐based analysis of high‐resolution MR images will confirm involvement of the brain in CFS, and in particular of the midbrain, prefrontal white matter and/or supraspinal autonomic control regions which include the brainstem and hypothalamus 3435.

MATERIALS AND METHODS

Subjects

Twenty‐seven CFS subjects aged between 19 to 46 years were recruited from community‐based specialist and general practice. They met both the Fukuda 1 and Canadian 36 criteria for CFS. They were subjected to a routine medical history and examination by one physician (R.B.), and a biochemical and haematological analysis and a resting 12‐lead electrocardiograph (ECG) were performed. All medications including ‘natural therapies’ were discontinued 2 weeks before their study week, except for paracetamol and oral contraceptives. Subjects with a history of chemical sensitivities or body mass index >30, or who were pregnant, postmenopausal, unable to undertake brain MR or cerebral SPECT scans, or unable to discontinue medication were excluded. The study period was delayed for any viral or bacterial infection until recovery.

Twenty‐seven normal controls (NC), unrelated to the CFS subjects, were recruited by public advertisement, and were matched for gender, age to within 2 years and weight to within 5 kg. They were not taking any medications and had no previous serious illnesses. All participants were compensated for transport costs alone. All examinations were completed within 1 week. The study protocol was approved by the Research Ethics Committee of the Royal Adelaide Hospital and all subjects gave informed written consent.

To determine levels of depression and anxiety all subjects completed the hospital anxiety and depression scale (HADS) questionnaire 37. Two CFS subjects and their age‐ and sex‐matched NC were removed from the analysis based on their MR scan. One male, aged 30 years, had an absent right cerebellum without cerebellar symptoms, and one female, aged 20 years, had a large frontal angiomatous tumour, again asymptomatic referable to the tumour. Thus, 25 CFS subjects and 25 NC were assessed with 6 males and 19 females in each group. Mean ages were 32 years (range 19 to 46) for CFS subjects and 32.8 years 2046 for NC.

CFS scores

Fatigue duration and two questionnaires were used to score CFS status.

First, the 10‐level Bell CFS disability scale 31 (Bell score), for which the subject selects the description that best fits their level of functioning.

Second, the 10 most common CFS symptoms present in more than 80% of CFS surveys were scored 2432, namely: severity of fatigue, change in sleeping pattern, dizziness on standing, pain in muscles, stomach symptoms, overall level of function, change in concentration, change in short‐term memory, headaches and experience of emotional swings.

In an interview conducted at the time of medical assessment by the same experienced clinician (R.B.) each symptom was scored on a 10‐point scale for all CFS and NC subjects. A score of 10 corresponded to no symptoms, and a score of 0 extremely severe. ‘Total symptom score’ was the sum of all 10 scores.

Haemodynamic scores

Twenty‐four‐hour ambulatory blood pressure monitoring was performed with an ‘Oscar 2’ sphygmomanometer (SunTech Medical, Morrisville, NC, USA) which was fitted in the home and retrieved the next day after 24‐h of recording. The cuff was inflated and systolic and diastolic blood pressures (BP) and heart rate were recorded every 30 min from 07.00 to 22.00 hours and hourly from 22.00 to 07.00 hours. Pulse pressure (PP = systolic – diastolic) was calculated at each time point. All parameters were averaged over actual ‘asleep’ and ‘seated’ sub‐periods from the written record of activity kept by the participants.

We also monitored haemodynamic autonomic function via blood pressure and heart rate responses to the stressors of postural change, Valsalva manoeuvre and hand grip. These results will be reported elsewhere.

Correlations between clinical scores

We performed an analysis of the correlations between all pairs of CFS and hemodynamic scores in the CFS and NC groups separat