- Open Access
A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior
BMC Medicine volume 11, Article number: 64 (2013)
It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions.
Humans and animals use a range of autonomic, metabolic and behavioral responses to combat acute infections or injuries. Sickness behavior is a physiological behavioral response principally induced and regulated by proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6 and tumor necrosis factor (TNF)α, which act centrally to induce sickness behaviors, including pyrexia. Proinflammatory cytokines modify the activity of hypothalamic neurons causing an increase of the thermoregulatory set point . In addition, animals and humans display symptoms such as fatigue, malaise, hyperalgesia, neurocognitive disorders, sleepiness, anhedonia, anorexia and weight loss, as well as diminished food intake, social activities, locomotor activity, grooming and exploration [2, 3]. Sickness behaviors are viewed as adaptive responses, which facilitate recovery from acute infections or injuries [2, 3]. Sickness behaviors, including fever, are postulated to offer a survival benefit in endothermic and ectothermic vertebrates . The sickness response is conserved by evolution and has an adaptive function in enabling survival of individuals and species in the face of assault by a myriad of microbial pathogens and injuries . Stereotypical patterns of sickness are displayed by mammals, birds, reptiles and even invertebrates . In summary, (a) this proinflammatory cytokine-induced sickness response is short lasting, evolutionarily conserved, and beneficial to the organism; and (b) many of the sickness behaviors are valuable in conserving energy and therefore to combat and attenuate the inflammatory response caused by infections or inflammatory trauma [3, 7].
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disorder that can have a greater impact on functional status and well-being than many other chronic, life-threatening diseases [8, 9]. ME/CFS is associated with a dramatic decrement in physical functioning  with patients scoring significantly lower on most of the eight Medical Outcome Study (MOS) 36-item Short-Form (SF-36) health survey subscales when compared with patients with cardiovascular and neurological disorders, as well as higher on depression measures . Typical symptoms of ME/CFS are: physical and mental fatigue, pain, muscle weakness, neurocognitive impairment, sleep disturbances, depression, gastrointestinal symptoms, a subjective feeling of infection or a flu-like malaise and post-exertion fatigue or malaise [11, 12].
Thus, there are important behavioral/symptomatic similarities between both ME/CFS and sickness behavior. Moreover, activated immunoinflammatory pathways play a role in the pathophysiology of ME/CFS, for example, increased proinflammatory cytokine levels . As such, both sickness behavior and ME/CFS share common phenomenological and biochemical aspects. These findings led some authors to conclude that ME/CFS and sickness behaviors are a manifestation of a common pathophysiology with other neurophysiological mechanisms of sickness behavior being similarly extrapolated to ME/CFS and related conditions . Other authors maintain that ME/CFS is fundamentally a more chronic version of acute sickness behavior . The latter authors in fact change the meaning of the term sickness behavior and use the term to describe a situation where the sickness behavioral complex and the inflammatory condition persist. This situation should then be recognized as persistent sickness behavior or ME/CFS.
A further confounding factor is the diagnosis and subtyping of ME/CFS. There are different diagnostic criteria used to make the diagnosis of ME/CFS, generating considerable controversy. According to a commonly used diagnostic classification for ME/CFS, Fukuda's criteria , ME/CFS is accompanied by chronic fatigue lasting for more than 6 months and at least four additional symptoms (sore throat, tender lymph nodes, neurocognitive disorders, multiple joint pain, muscle pain, headache, non-refreshing sleep or post-exertion malaise (PEM) lasting more than 24 h). The diagnosis of ME/CFS according to Fukuda's criteria, however, defines a heterogeneous group of patients . Recently, we have provided evidence suggesting that ME/CFS patients should be divided into those with and without post-exertion malaise into ME and CFS, respectively. Doing so, it was defined that ME and CFS are qualitatively distinct diagnostic classes .
Another major confound is the common perspective within psychosocial psychiatry to consider ME/CFS as a condition triggered by excessive rest in predisposed individuals following acute triggers . This perspective places ME/CFS within a psychosocial and psychiatric framework. Recently, we have incorporated aspects of this within a biological model with psychosocial aspects contributing to, and themselves being driven by, inflammatory and related pathways, providing a more parsimonious explanation based on biological underpinnings .
In the present work, we review: (a) the phenomenological similarities and dissimilarities between sickness behavior and ME/CFS, (b) the course of sickness behavior versus ME/CFS, (c) the immunoinflammatory-related pathways that underpin or may discriminate both sickness and ME/CFS, and (d) the differences in etiologic factors that trigger both conditions.
Phenomenological similarities between sickness behavior and ME/CFS
Symptoms typical of sickness behavior are described above. The phenomenological experience of acute viral or bacterial infection involves malaise, a lack of motivation or lassitude, with accompanying fatigue bordering on exhaustion. Other responses include numbness, shivering, impaired appetite and weight loss, as well as aches and pains in muscles and joints .
Table 1 summarizes the similarities and dissimilarities between sickness behavior and ME/CFS. People with ME/CFS have a wide range of classically conceptualized psychosomatic, but recently reframed physiosomatic, symptoms [11–13]. Typical symptoms include fatigue and chronic exhaustion. These symptoms include unrelenting severe disabling mental and physical fatigue combined with disabling levels of muscle fatiguability. Hyperalgesia, muscle pain and tension, migraine type headaches, insomnia, hypersomnia, non-refreshing sleep or sleep wake cycle reversal are typical symptoms of ME/CFS. Problems with memory retrieval can manifest as an inability to finish sentences, negatively feeding back on self-esteem and subjective wellbeing. These symptoms are exacerbated by cognitive and or physical activity. Intolerance to even trivial increases in physical or mental activity above individual norms is the hallmark symptom of ME [10–12, 17, 18]. This intolerance manifests itself as marked worsening of symptoms that may be short lived or prolonged (sometimes weeks) but only rarely resulting in permanent disability [10, 11]. Post-exertion malaise indicates the intense malaise, exhaustion or neurocognitive symptoms following physical or mental activities and lasting for more than 24 h. This typical symptom in ME corresponds with the fatigue and exhaustion behaviors expressed during sickness behavior.
Malaise, a key aspect of sickness behavior, is also a major feature of ME/CFS. Many individuals with ME/CFS display symptoms normally associated with severe influenza, for example, including a flu-like malaise or the subjective feeling of infection . This symptom scores highly on two symptomatic dimensions of ME/CFS pathology; that is, a sickness dimension that loads highly on neurocognitive disorders, depression, and autonomic disorders and a hyperalgesia dimension that loads highly on muscle pain and tension and headache. This could be seen as analogous to the malaise theory of depression, which considers malaise as a key feature of depression , which we have recently shown could not be validated, as only some depressed patients experience malaise . However, this highlights the phenomenological and biochemical overlaps among depression, somatization and ME/CFS .
Depressive-like behaviors, including reduction of locomotor activity, anhedonia (reduced intake of sweetened milk in rodent models), anorexia and weight loss are characteristics of sickness behavior and are not specific to ME/CFS. However, there are high rates of comorbidity between ME/CFS and depression. Subclinical and full-blown clinical depression frequently accompany ME/CFS . Moreover, measures of clinical depression and ME/CFS show high comorbidity, with clinical depression being the most prevalent comorbidity with ME/CFS in some studies . This has led some to propose that ME/CFS is a form of clinical depression . In addition, depressive symptoms, such as sadness, are included in rating scales, such as the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale . Thus, in fact, patients with ME/CFS may have anorexia, weight loss, and so on, when they also have clinical depression. However, clusters of physiosomatic symptoms coupled to increases in immunoinflammatory pathways are significant commonalities in depression and ME/CFS, suggesting significant phenomenological and biochemical similarities that may be relevant to overlaps in subtyping and treatment . Nevertheless, clinical depression and ME/CFS are different syndromes, which may be discriminated with a high predictive value using severity of post-exertion malaise, percentage of time fatigue reported, shortness of breath, unrefreshing sleep, confusion/disorientation and self-reproach .
Other differences between sickness behavior and ME/CFS are pyrexia and gastrointestinal symptoms. Pyrexia is one of the key symptoms of sickness behavior and plays a role in the defense against acute infections and acute injury. Mild and moderate fever prevents viral replication and enhances crucial functions of polymorphonuclear leukocytes, including mobility and killing of bacteria . The effects of proinflammatory and cell-mediated immune (CMI) cytokines, including interferons, are more active during fever . There is, however, no evidence of pyrexia in ME/CFS. Nevertheless, the onset of ME/CFS as defined by fatigue, arthralgias, myalgias and a chilly sensation may be accompanied by low-grade pyrexia . In a small proportion of fatigued individuals, fatigue and isolated fever may apparently persist without organic pathology . In contrast to sickness behavior, many patients with ME/CFS have gastrointestinal symptoms as measured by the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale . Gastrointestinal symptoms, reminiscent of irritable bowel syndrome (IBS), are considered to be diagnostic criteria in new ME and ME/CFS case definitions [10, 11]. In addition, these gastrointestinal symptoms may have a specific inflammatory pathophysiology, including via increased bacterial translocation .
ME/CFS patients display signs of autonomic nervous system dysfunction [28, 29] and although not typically described as core symptoms of sickness behavior these symptoms may also occur during acute inflammatory conditions. Neurally mediated hypotension and orthostatic intolerance are the most commonly documented cardiovascular symptoms in ME/CFS. The latter abnormality in particular correlates with the severity of disease [30, 31]. Postural orthostatic tachycardia syndrome is another common finding. Exaggerated postural tachycardia and enhanced sympathetic activity have been reported . Intolerance of wide temperature changes and markedly impaired thermostatic stability are other commonly reported manifestations of autonomic dysfunction. A subdued cardiac response to exercise has been reported  and sympathetic hyperactivity coupled with reduced vagal modulation are reproducible findings . De Becker et al.  detected a sympathetic drive mediated increased heart rate on tilt compared to healthy controls. Another study demonstrated impaired heart rate responses to exercise coupled with globally impaired hemodynamic responses incompatible with patient deconditioning or prolonged inactivity . Several other authors have reported autonomic dysfunctions in people with ME/CFS [36–38].
In summary, cross-sectionally there is a phenomenological overlap between sickness behavior and ME/CFS, both presenting with malaise, hyperalgesia, fatigue, exhaustion, sleepiness, failure to concentrate, and sometimes mood disturbances. PEM following mental and physical activities, a characteristic symptom of ME, may also occur during sickness behavior. Other symptoms or behaviors, however, discriminate ME/CFS and sickness behavior. For example, gastrointestinal symptoms reminiscent of IBS [10, 11] occur in many ME/CFS patients but not typically in sickness behavior. Anorexia and weight loss, typical symptoms of sickness, are not germane to ME/CFS unless there is comorbid depression. While pyrexia is a hallmark of the acute inflammation during sickness, mild fever may occur in a small proportion of ME/CFS patients. Phenomenologically, the acute sickness response demonstrates some overlap with ME/CFS but the range of symptoms experienced by people with ME/CFS is much wider than in sickness behavior.
Course: sickness behavior versus ME/CFS
Sickness behavior is conceptualized as a short-term response to acute infections or injuries. Sickness is an adaptive behavioral response that is appropriate to counteract acute bacterial or viral infections or inflammatory trauma and therefore plays a role in the resolution of inflammation and thus recovery. ME/CFS, on the contrary, is an enduring disorder with a relapsing-remitting or chronic course [12, 39]. Using international consensus criteria for ME/CFS, most studies report a waxing and waning or progressive pattern of this disease [40–42]. In contrast to sickness behavior, which is a short-lasting, beneficial behavioral response, the recovery rate from ME/CFS is very low [40–42]. For example, in studies using CDC criteria the recovery rate was only 4% [40, 42]. In another prospective study carried out over 12 months, none of the patients recovered, while 40% of the individuals with ME/CFS did not improve, 20% showed a progressive course, and 40% showed a relative improvement in their symptoms .
Recent use of the terms prolonged, persistent or inappropriately sickness behavior has emerged. Within this terminological perspective, ME/CFS and sickness behavior may be regarded as manifestations of a shared pathophysiology, with ME/CFS viewed as an expression of persistent increases in proinflammatory cytokines following an episode of acute inflammation. We have argued that attaching the terms prolonged, exaggerated or persistent to sickness behavior is unsatisfactory, primarily due to sickness behavior by definition, being a short-lasting, beneficial behavioral response that plays a role in the resolution of inflammation . As discussed above, some authors consider that the sickness responses may persist when the production of proinflammatory cytokines, for example following gut and hepatic inflammation or choleostasis, is no longer restricted to the periphery, but also becomes established systematically, and perhaps prolonged, within the CNS [44–46]. Prolonged fatigue and depression, however, are not generally viewed as adaptive behaviors but are more parsimoniously seen as dysfunctional  as is the case in autoimmune disorders or persistent infections. Therefore, these conditions cannot be termed sickness behavior (defined as an acute adaptive response), with these patients more likely to have secondary depression, CFS or ME perhaps as a result of pre-existing genetic or epigenetic priming that alters the longer-term consequences of infection and other stressors.
'Persistence' of inflammation is in our opinion not an adequate term and should better be labeled as 'transition from an acute inflammatory response to a chronic inflammatory state'. The 'transition' label stresses that the pathways underpinning the pathophysiology of chronic inflammation and chronic inflammatory disease are distinct from the beneficial mechanisms that determine sickness behavior . In this respect it was shown that such transition towards chronic inflammatory conditions may play a role not only in ME/CFS but across a range of different diseases, for example, post-trauma illness, malaria, sepsis, and so on . There is a further overlap between sickness behavior as a physiological construct, and abnormal illness behavior as a psychological/behavioral construct. The latter overlaps with illness investment and the sick role, and may be concurrent or overlapping phenomena .
In summary, while sickness behavior is a short-lasting, adaptive and acute inflammatory state, ME/CFS is a chronic disorder characterized by a waxing and waning or progressive pattern with an extremely low recovery rate (see Table 1).
Neuroimmune pathways in sickness behavior and ME/CFS
Energy metabolism in sickness behavior versus ME/CFS
Acute inflammatory conditions consume large amounts of energy, whereby adipose and muscle tissues and glycogen are used to provide energy to combat pathogens . This causes a negative energy balance; that is, the expended usage of calories is greater than the intake. Lowered synthesis of muscle proteins, proteolysis, and lipolysis and loss of tissue proteins and fats are typically induced by proinflammatory cytokines produced in response to invading pathogens in injured tissues . The objective of the sickness response from an evolutionary perspective is energy conservation [3, 7, 15]. Proinflammatory cytokines, such as TNFα, not only modulate a negative energy balance to compensate for the increased energy demands but also reduce food intake by causing anorexia and decreased voluntary energy utilization . Characteristic sickness behavior symptoms, such as lethargy, sleepiness, fatigue, listlessness, malaise, hyperalgesia, psychomotor retardation, loss of libido and cognitive deficits aim to limit highly energy-consuming processes, such as motor, sexual and brain activities . As such, energy that otherwise would be consumed for locomotor, reproductive and neurocognitive activities is withdrawn from the brain, muscles and other peripheral tissues and redirected to fuel the calorie-dependent activities of immune cells [2, 3, 7, 15]. Thus, the typical sickness behaviors save energy and contribute to redirecting the conserved energy to immune cells as well as to pyrogenic and other inflammatory processes. As such, sickness behaviors, in shifting resources to a patterned immune response, help to combat acute infection or injury.
Moreover, by inducing anorexia (and thus restricting calorie intake), intracellular signaling pathways associated with inflammation are attenuated. This includes those leading to IL-6 production . Calorie restriction additionally attenuates lipopolysaccharide (LPS)-induced sickness behavior in a dose-dependent manner . Therefore, we have argued that sickness behavior is part of the compensatory (anti)-inflammatory reflex system (CIRS), which is induced in response to inflammatory processes . Thus, sickness behavior augments the beneficial effects of inflammation and at the same time limits an overzealous inflammatory response [3, 50]. The increased energy expenditure and anorexia leading to the negative energy balance eventually causes loss of body fat, protein mass and thus lean body mass and therefore may lead to inflammation-associated weight loss . Weight loss results in anti-inflammatory effects attenuating the production of, for example, IL-6 and TNFα and increasing that of endogenous anti-inflammatory compounds, for example, adiponectin . Thus, not only proinflammatory cytokine-induced anorexia but also the consequent weight loss is a homeostatic adaptive response, which should be considered as part of the CIRS .
Finally, energy saving sickness behaviors, such as fatigue, listlessness, loss of libido, and neurocognitive disorders, not only play a role in the resolution of inflammation but are crucial in preventing the transition from acute to chronic inflammation. Thus, by saving energy and compensating for the negative energy balance sickness behaviors prevent inflammatory sequelae, such as depletion of energy stores, cachexia, anemia, osteopenia and insulin resistance, which determine the transition towards chronic inflammation . The transition from acute to chronic inflammation occurs around 19 to 43 days after the onset of the acute phase of inflammation . Chronic inflammation ensues when the acute inflammatory response and the CIRS, including sickness behavior, were not able to eradicate the primary infectious agent or heal the injury, for example, pyogenic bacteria, viral infections, fungi, sarcoidosis, and autoimmune responses .
ME/CFS, however, is a chronic disease, which is accompanied by an inability to generate energy on demand . Mitochondrial dysfunctions and abnormally low ATP and high lactate levels play a role in ME/CFS [12, 53–61]. ME/CFS patients display exercise-induced exhaustion much earlier than healthy controls. When reaching exhaustion, ME/CFS patients display diminished intracellular ATP and dysregulated oxidative metabolism, coupled to increased glycolysis in the exercising striated muscles [12, 58]. ME/CFS patients display reduced rates of ATP resynthesis in the aftermath of exercise versus controls resulting from impaired oxidative phosphorylation . Patients with ME/CFS show prolonged elevations of lactate, returning extremely slowly to normal levels [53, 59]. Behan et al.  found histopathological abnormalities in the mitochondria of skeletal muscles in ME/CFS. During exercise, the latter display decreased voluntary muscle contractions, which worsen subsequently . Thus, in ME/CFS patients reduced intracellular ATP, oxidative metabolism and accelerated glycolysis in skeletal muscles determine early exhaustion [12, 58, 61]. Several studies report significantly increased levels of ventricular lactate in ME/CFS patients, suggesting central energy dysregulation [62, 63].
We previously proposed that the defects in energy production and mitochondrial functions in ME/CFS are probably caused by chronic inflammatory and oxidative and nitrosative stress (O&NS) processes [12, 58]. Thus, raised levels of proinflammatory cytokines resulting from systemic inflammation disable oxidative phosphorylation within mitochondria. This is reflected in the increased lactate and mitochondrial dysfunction commonly seen in chronic inflammatory states . For example, TNFα causes a marked decrease in mitochondrial membrane potential, which may increase reactive oxygen species (ROS)  and increases mitochondrial membrane permeability leading to membrane depolarization . Increased ROS damages the electron transport chain leading to depleted ATP production, which in turn causes a deficiency in oxidative phosphorylation leading to overt mitochondrial disease . Defects in oxidative phosphorylation leads to increased ROS production, which acts to create self-propagating mitochondrial dysfunction  contributing to increased IL-1β and IL-18 via inflammasome induction . Mitochondrial shutdown induced by proinflammatory cytokines is ultimately engineered by nitric oxide (NO) and is reversible . NO signaling regulates mitochondrial number and function  and inhibits mitochondrial respiration  by competing with oxygen at complex 1 and cytochrome oxidase  resulting in diminished ATP production. Peroxynitrite inhibits mitochondrial respiration by modulating electron transport complexes I and III . Attenuation of mitochondrial respiration by for example NO or its derivatives activates ROS and reactive nitrogen species (RNS) produced by mitochondria . In addition, the increased levels of nuclear factor (NF)κB observed in ME/CFS  contribute to a shift towards aerobic glycolysis (the Warburg effect) as observed in cancer cells .
Kennedy et al.  reported elevated surrogate biomarkers of O&NS in ME/CFS, which positively associated with symptom exacerbation following energy expenditure. Fatigue results from ROS accumulation and diminished availability of ATP in muscle cells . As to how this relates to the putative subtypes of Booth et al. , where ME/CFS patients are subdivided on the basis of decreased ADP uptake by mitochondria versus decreased ATP output requires further investigation. These two subgroups are predicted to differentially show increased lactate production and altered ability for repeat exercise. It is not unlikely that changes in oxidative status, lipid peroxidation and mitochondrial membrane rigidity are impacting on the activity of the ADP-ATP translocator (TL), perhaps having differential effects on TL uptake or output functions. Around 20% of mitochondria in cells at any given point in time are in the process of transport, either exhausted and being removed from sites of high-energy need or fresh mitochondria are being imported into such sites. Further investigation is required as to whether the energetic changes in mitochondria in ME/CFS contribute to dysregulated signaling for transport. This may overlap with the genetic susceptibility to ME/CFS mediated by changes in the disrupted-in-schizophrenia 1 (DISC1) gene, which is associated with mitochondrial transport . ATP is also an important neuronal and glia transmitter. As to how altered mitochondrial ATP regulation modulates such wider ATP functions is unknown, but would be expected to contribute to cognitive deficits, especially in high energy demand activities of the ventral lateral prefrontal cortex that are required to unhook specific memory exemplars.
In summary, energy metabolism plays a key role in sickness behavior and ME/CFS and also differentiates sickness from ME/CFS. Table 1 and Figure 1 show the differences in energy metabolism between both conditions. Thus, sickness behaviors aim to conserve and redirect energy to immune cells, preventing transition from acute to chronic inflammation. ME/CFS, however, shows chronic dysfunctions in ATP and lactate production, caused by peripheral and central mitochondrial dysfunctions, driven, in part, by chronic inflammation and O&NS.
Immunoinflammatory pathways in sickness versus ME/CFS
Elevated levels of proinflammatory cytokines drive most if not all aspects of the sickness response either directly or indirectly . Proinflammatory cytokines, including IL-1, IL-6, and TNFα, activate the production and/or release of secondary inflammatory mediators, such as prostaglandins (PGs) and NO . Proinflammatory cytokines directly stimulate numerous neurohormonal systems. A variety of mechanisms allow proinflammatory cytokine signals to circumnavigate of the blood brain barrier . Blood borne proinflammatory cytokines can diffuse through relatively permeable areas of the blood brain barrier via the circumventricular organs , allowing proinflammatory cytokines to directly interact with microglia and astrocytes in the glia limitans. Another crucial pathway involves a complex series of interactions between proinflammatory cytokines and brain endothelial cells . The third pathway involves the activation of neurons by proinflammatory cytokines via the vagus nerve and catecholaminergic circuits of the sympathetic nervous system (SNS) . (For a more detailed examination of immune to brain communication, see .) Interestingly, the production of TNFα persists in the brain much longer than in the periphery [84–86], while TNFα additionally passes both ways across the blood-brain barrier . This is concordant with chronic neuroinflammation and low-grade peripheral inflammation being interconnected phenomena. Within the brain, proinflammatory cytokines, prostaglandins and NO invoke brain responses to infection in the periphery . Once microglia are activated, astrocytes are recruited leading to further activation of neuroinflammatory signals . Thus, both cell types collaborate to propagate neuroinflammation and the physiological changes directed at diminishing the replication of pathogens increasing the metabolism of carbohydrate fat and protein  and generating energy-conserving behaviors .
The central nervous system (CNS) modulates the immune response via two pathways: (a) the hypothalamic-pituitary-adrenal (HPA) axis and (b) the release of catecholamines and acetylcholine . Communication of proinflammatory cytokine signaling to the brain via the vagus provokes a rapid anti-inflammatory response through increased HPA axis and cholinergic nerve activity . This forms the basis of the CIRS response including the HPA axis, cholinergic and anti-inflammatory responses . This CIRS response in the CNS and autonomous nervous system generates its own characteristic symptom pattern (for example, autonomic symptoms) and is thus part of the sickness response. The SNS modulates the immune response at systemic, local and regional levels . Catecholamines inhibit production of proinflammatory and T helper (Th)1 cytokines, while enhancing the synthesis of Th2 cytokines together with IL-10 and transforming growth factor (TGF) 1 . Acetylcholine release through activation of the parasympathetic nervous system attenuates the production of IL-1, TNFα and IL-6 .
Such mechanisms underpinning the sickness response reveals it as an automated irresistibly integrated response conserved by evolution and which is induced by proinflammatory cytokines, including IL-1 and TNFα. The relation between elevated proinflammatory cytokines and fatigue and fatiguability is well documented . Elevated proinflammatory cytokines are largely responsible for the severe fatigue seen in multiple sclerosis , cancer-related fatigue and cognitive symptoms , fatigued breast cancer survivors , and the debilitating fatigue reported by underperforming athletes . Inhibition of IL-1β is associated with a 50% reduction in fatigue in patients with Sjögren's syndrome . Proinflammatory cytokines and prostaglandin E2 (PGE2) mediate inflammatory hyperalgesia  as well as neurocognitive abnormalities leading to problems with concentration and memory [95, 101]. Many of these adverse effects especially in the CNS are mediated by IL-1β . The hippocampus is the hub of processes involving learning and memory and is also the region of the brain with the highest levels of IL-1 receptors and is especially vulnerable to the effects of neuroinflammation . While physiological levels of IL-1 are essential in the development of memory and learning, elevated endogenous levels results in neurocognitive dysfunctions and abnormal behaviors [104, 105]. IL-1β also mediates the suppression of feeding behavior and appears to regulate lipid metabolism by antagonizing the performance of lipoprotein lipase, which is the principal regulator of lipid store mobilization in the body . IL-1β and NFκB are essential mediators of the anhedonic effects of sickness behaviors . Moreover, IL-1β in concert with TNFα inhibits sexual behavior . TNFα and IL-1β suppress the clock genes that regulate circadian rhythm and hence could influence a veritable myriad of biological functions. The net effect of the action of these cytokines on clock genes is to reduce the metabolic rate and the demand for energy in the form of ATP .
In patients with ME/CFS, proinflammatory cytokines, including IL-1β and TNFα, are elevated and are significantly associated with the severity of fatigue, a flu-like malaise, sadness and autonomic symptoms . This together with the findings that these proinflammatory cytokines may cause similar sickness behaviors suggest that increased levels of proinflammatory cytokines may contribute to selected ME/CFS symptoms . However, in ME/CFS activation of immunoinflammatory pathways and intracellular signaling networks, including NFκB, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) and CMI pathways contribute to fatigue, malaise, hyperalgesia, and autonomic and neurocognitive symptoms [12, 13, 95]. Moreover, there are many more immunoinflammatory related differences between sickness behavior and ME/CFS, including the following.
Elevated levels of proinflammatory cytokines may be associated with a number of other biological disorders that are observed in ME/CFS. For example, as explained in the previous section, TNFα affects energy metabolisms and leads to defects in mitochondria. TNFα also reduces the number of mitochondrial cristae and inhibits mitochondrial respiration. TNFα causes opening of mitochondrial permeability transition pores (PTP) leading to a disappearance of the inner membrane potential and the uncoupling of oxidative phosphorylation . Proinflammatory cytokines also induce O&NS pathways and by generating an increase in ROS in the electron transport chain deplete glutathione . Proinflammatory cytokine elevations in general lead to the upregulation of NADPH oxidase , generating superoxide anions and reactive oxygen dependent damage, ultimately leading to the formation of peroxinitrite and membrane damage by lipid peroxidation [111, 112]. IL-6 also dramatically increases the rate of glucose usage in striated muscle .
Numerous immunoinflammatory abnormalities are also seen in people with ME/CFS indicating an activated but dysregulated immune system, including high levels of serum neopterin [13, 95], which is a surrogate marker for increased interferon (IFN)γ levels . High neopterin concentrations occur in diseases with activated Th1 type immune responses, including viral infections, a number of autoimmune diseases and several neurodegenerative diseases . Elevated IFNγ levels deplete tryptophan in the plasma and the brain via activation of indoleamine-2,3-dioxygenase as can be observed in chronic active viral infection .
It is worth emphasizing at this point that much of the symptoms and pathology driven by proinflammatory cytokines occurs transiently in sickness behavior, but occurs chronically in ME/CFS. Far from being a Th2 dominated illness it is now clear that Th1 and Th2 cytokines coexist in ME/CFS [12, 58]. Moreover, the cytokine profile in ME/CFS patients changes markedly over time . Chronic elevation of Th2 and Th1 cytokines may conspire to create additional and more complex pathologies, for example, accelerating the rate of glucose homeostasis in the brain . Other well documented immune abnormalities in ME/CFS, which are not germane to sickness behavior, include dysregulated forkhead box P3 (FoxP3) expression , disrupted T cell homeostasis as indicated by reports of increased CD26 expression , decreased expression of CD69  and elevated B cell numbers .
A plethora of other immune abnormalities have been detected in patients with ME/CFS, which when taken together demonstrate the existence of a dysregulated immune system. These findings include reduced natural killer cell function and T cell exhaustion [12, 58, 119–122]. T cell exhaustion and the Th2 response may suggest that ME/CFS is accompanied by activation of the CIRS, as can be observed in many other inflammatory disorders [3, 12].
In summary, there is some evidence that shared inflammatory pathways (that is, increased proinflammatory cytokine levels) underpin sickness behavior and determine part of the symptoms in ME/CFS (see also Table 1). However, while sickness behavior is a beneficial response induced by proinflammatory cytokines to conserve energy and combat pathogens thus preventing transition to chronic inflammation, ME/CFS is a chronic inflammatory disorder accompanied by a combined Th1 and Th2 response and multiple signs of a seriously dysregulated immune system.
O&NS pathways in sickness versus ME/CFS
Other pathways that discriminate sickness behavior from chronic inflammatory disorders are reduced antioxidant levels and increased O&NS, driving O&NS damage to lipids, DNA, proteins and mitochondria (see above). Inflammatory processes, CMI activation and O&NS processes are inseparably associated. For example, phagocytes and activated M1 macrophages produce large amounts of ROS and RNS . CMI activation produces neopterin, increasing ROS and RNS . O&NS processes also activate the production of proinflammatory cytokines and T cells . Therefore sickness behavior may be accompanied by elevated levels of ROS/RNS, which help to eradicate invading pathogens, that then normalize with the resolution of inflammation.
ME/CFS, however, shows chronically increased ROS/RNS, O&NS processes and O&NS damage, including increased malondialdehyde (MDA), isoprostane, 2,3 diphosphoglyceric acid, 8-OH-deoxyguanosine, protein carbonyls and thiobutyric acid [126–130]. iNOS production is significantly higher in ME/CFS patients versus controls . As discussed in the next section, ME/CFS is accompanied by a chronic hyperproduction of NO [95, 126]. Raised oxidative stress levels also occur in response to exercise in ME/CFS  potentially explaining one of the mechanisms underlying post-exertion malaise . Skeletal muscle oxidative imbalance contributes to increased muscle fatiguability .
Lowered levels of coenzyme Q10, zinc and glutathione have been reported in ME/CFS [126, 127, 131] with amelioration of oxidative stress occurring during remission . As well as decreased coenzyme Q10 , decreased vitamin C and E will impact mitochondrial function, increasing lipid peroxidation. Such effects are potentially prevented by melatonin , as shown after strenuous exercise in humans . Maes et al.  reported significantly increased ω6 lineolic and arachidonic acids in ME/CFS, driving a reduced ω3 to ω6 polyunsaturated fatty acids (PUFAs) ratio versus controls, contributing to inflammation in ME/CFS .
Such alterations can generate pathology via a number of mechanisms. Isoprostane, a prostaglandin (PG)F2-like compound, correlates positively and significantly with general ME/CFS disease severity as well as the magnitude of exercise induced disease exacerbation . Elevated MDA promotes phospholipids rigidity, altering membrane fluidity, permeability and transport mechanisms . Importantly, elevated MDA decreases mitochondrial membrane fluidity . A decrease in melatonin, found in some ME/CFS studies, would contribute to increased mitochondrial membrane rigidity , as well as reduced natural killer cell activity in ME/CFS . Melatonin also modulates aspects of sickness behaviors , inhibiting NFκB induction and microglia activation , suggesting that variations in melatonin may confound the comparison of processes in ME/CFS and sickness behavior.
In summary, while sickness behavior is probably accompanied by increased ROS/RNS, which should normalize upon the resolution of inflammation, ME/CFS is accompanied by chronically activated O&NS processes causing chronic damage to lipids, DNA, proteins and mitochondria. While in sickness behavior the putative increase in ROS/RNS would be an adaptive response, increased O&NS largely underpins the pathophysiology of ME/CFS.
Autoimmune responses in ME/CFS
Autoimmune processes also frequently occur in ME/CFS and are not germane to a beneficial short-term response as sickness behavior. IgM autoimmune responses directed against oxidatively damaged lipid membrane components (for example, oleic acid), anchorage molecules (for example, palmitic and myristic acid and S-farnesyl-L-cysteine), residue molecules of lipid peroxidation (for example, azelaic acid and MDA), and amino acids or proteins modified by nitrosylating species (for example, NO-tyrosine, NO-phenylalanine, NO-tryptophan, NO-arginine, and NO-cysteine) have all been reported [12, 126]. These reactions are directed against neoantigenic determinants (neoepitopes), which are created as a result of damage to lipids and proteins by O&NS [12, 126, 141]. These antigenic structures are normally invisible to the immune system but become targeted because structural modifications induced by elevated O&NS have rendered them immunogenic. The levels of these corrupted entities correlate positively and significantly with the severity of selected ME/CFS symptoms, such as fatigue, muscle pain, a flu-like malaise, and so on [12, 126].
Reports of frank autoimmune reactions are commonplace in people with ME/CFS. Antibodies to cardiolipin, nuclear envelope antigens and neuronal antigens have all been reported [12, 142–145]. Several teams have reported elevated titers of autoantibodies directed towards gangliosides, serotonin, phospholipids, anti-68/48K and microtubule associated proteome as well as anti-lamin single stranded DNA [145–147]. Autoantibodies against muscarinic cholinergic receptors, mu-opioid receptors and dopamine receptors have been detected . Autoantibodies directed against ganglioside M1, for example, play a role in neuroimmune disorders, correlating with neurocognitive dysfunctions as observed in neuropsychiatric systemic lupus erythematosus [149, 150].
HPA axis function in sickness and ME/CFS
Sickness behaviors induced by different challenges and in different species are accompanied by marginally increased to significantly increased plasma corticosterone levels . Moreover, corticosterone causes sensitization of LPS-induced pyrexia and pain, but not lethargy, and leads to enhanced sickness-induced neuroinflammation . IL-1, via upregulation of prostaglandin and COX enzymes, enhances HPA axis activation  and hypothalamic norepinephrine synthesis . IL-1β also increases brain tryptophan concentrations and the rate of 5- hydroxytryptamine (5-HT) metabolism, which may further activate the HPA axis . Given glucocorticoid anti-inflammatory effects, HPA axis activation is part of the CIRS response . Glucocorticoids also significantly regulate immune genes and cell functions, for example, decreasing the Th1/Th2 ratio . Moreover, glucocorticoids participate in programmed cell death and energy-related processes, for example, glucose, lipid, protein and carbohydrate homeostasis [155, 156].
The activation of the HPA axis in sickness behavior contrasts the findings in ME/CFS. HPA axis hypoactivity is a characteristic feature in some people with ME/CFS [157, 158], for example, low baseline levels of HPA axis hormones, aberrant diurnal hormone levels, reduced HPA axis responses to provocation by corticotropin-releasing hormone (CRH) or adrenocorticotropic hormone (ACTH), blunted HPA axis responses to physical and psychological stress, and enhanced sensitivity to glucocorticoids [159–165]. This lowered HPA activity may be explained by prolonged stimulation of O&NS and immunoinflammatory pathways in ME/CFS. For example, chronic elevations of IL-6 may blunt the release of ACTH . TNFα may inhibit the stimulation of CRH, ACTH-induced cortisol release and adrenal gland function [167, 168].
In summary, while sickness behavior is accompanied by HPA axis activation as part of a CIRS, ME/CFS is accompanied by lowered HPA axis activity, which may be secondary to activation of immunoinflammatory and O&NS pathways (see Table 1).
Leptin: sickness versus ME/CFS
Leptin is an important mediator of infection-induced inflammation and sickness behaviors [169, 170]. However, leptin also accelerates the recovery from hypoxia-induced sickness behavior via an increase in IL-1 receptor antagonist (IL-1RA) . Obese rodents show an altered inflammatory and behavioral response to infection .
Treatment of ME/CFS with low dose hydrocortisone increases leptin, leading to a favorable treatment response . Interestingly, recent data shows leptin as a risk factor for, and displaying efficacy in the treatment of depression, as well as Alzheimer's disease [174–176]. Leptin, like melatonin, is a wide immune regulator, increasing natural killer cell activity and Th1 responses, while inhibiting the cAMP induction of tryptophan 2,3-dioxygenase (TDO) in astrocytes, thereby inhibiting cognitive deficits mediated by TDO induction of kynurenic acid. The severity of ME/CFS is associated with increased indicants of metabolic syndrome , suggesting that wider metabolic dysregulation associated with obesity and leptin resistance will modulate the course and perhaps etiology of ME/CFS. Thus, leptin may have significant and differential regulatory effects in ME/CFS and sickness behaviors.
Trigger factors in sickness behavior and ME/CFS
Sickness behavior is an adaptive CIRS response induced by acute injuries or bacterial and viral infections. These phenomenological experiences combined with pyrexia and neuroendocrine changes represent an integrated hierarchal system conserved by evolution to combat infection, conserve energy, play a role in the resolution of inflammation and limit an overzealous inflammatory response . When resolution of inflammation is not induced or when the inflammatory response is overzealous, a chronic inflammatory state may emerge [52, 178]. The consequent chronic inflammatory state is then localized where the trigger, either infection or injury, was present leading to persistent infections and medical disorders related to the affected organs or systemic immunoinflammatory and O&NS responses [3, 179].
In contrast to the role of acute infection/injury in sickness behavior, different trigger factors such as acute and chronic infections, environmental factors and other medical disorders may play a role in ME/CFS. Depending on the applied case definitions, the presence of medical illnesses may sometimes be regarded as exclusion criteria for a diagnosis of CFS . Thus, Fukuda's criteria consider that the fatigue should not be caused by any conditions that may be identified by specific tests or diagnoses . Other criteria however make the presence of neuroendocrine symptoms and intolerance of mental or physical exercise mandatory . The latter authors propose that a strategy be developed which could detect patients with a neuroimmune condition rather than focus on patient populations that have fatigue whose origin is not revealed by routine medical testing or explained by any psychiatric condition. Moreover, we have argued that ME/CFS may be caused by other inflammatory disorders, including multiple sclerosis, autoimmune disorders, and so on, and that in these conditions also the diagnosis ME/CFS or ME/CFS due to general medical condition should be made [12, 17].
Upper respiratory system and flu-like infections often precede the onset of ME/CFS . ME/CFS often occurs in epidemics suggesting that infections may cause ME/CFS . Bacterial and viral infections, including Epstein-Barr virus (EBV), Coxiella burnetii, Parvo B19 and Mycoplasma, are well known trigger factors associated with the onset of ME/CFS . However, infections not only trigger ME/CFS but may also function as maintaining factors. Thus, many patients with ME/CFS have persistent, recurrent or opportunistic bacterial and viral infections [183, 184]. These infections may maintain ME/CFS or cause relapses . Moreover, the number and severity of symptoms, including neurological symptoms, is correlated with the existence of concurrent infections [186, 187]. Gene expression data show latent viral or bacterial infections in ME/CFS, for example, Epstein-Barr virus, enteroviruses and C. burnetii [188–190]. Other infections that are associated with this disorder are, among others, human herpesvirus (HHV) 6 and 7, cytomegalovirus, enteroviruses, Borna disease virus, Chlamydia pneumoniae and Borrelia burgdorferi .
In summary, sickness behavior and ME/CFS are related to infections. One major difference, however, is that sickness behavior is a short-lasting, adaptive response to acute infection, whereas recurrent or opportunistic infections play a role in the severity and in the relapsing and chronic course of ME/CFS. While sickness behavior is caused by acute infections, the onset of ME/CFS may sometimes be associated with the long-term effects of an acute infection, such as long-standing neuroinflammation, O&NS processes or the onset of autoimmune reactions. Moreover, it is probable that when an initial infection is not cleared and/or there was no resolution of inflammation, a chronic infection with activation of immunoinflammatory and O&NS processes may ensue. Arguably these processes may be associated with the onset of ME/CFS. By inference, in some patients who initially showed sickness behaviors in response to an acute infection, ME/CFS may develop. From a clinical point of view, the transition from acute (sickness behavior) to chronic inflammation occurs between 19 to 43 days. According to the diagnostic criteria of ME and CFS [10, 16], the patient cannot be diagnosed as having ME/CFS until 6 months after the onset of the disease. This means that patients, even when experiencing chronic inflammatory processes and from ME/CFS symptoms, cannot be diagnosed as ME/CFS between days 19 to 43 and 6 months. Prolonged or persistent sickness behaviors for this period are not adequate labels because sickness behavior denotes an adaptive and acute inflammatory response, whereas the patients after 19 to 43 days are already in a chronic inflammatory state. Therefore, we propose that those patients should be categorized as having chronic fatigue (CF), a diagnosis which then should be changed into CFS or ME some months later .
In contrast to sickness behavior, the initial trigger in ME/CFS is not always well defined, while the chronic stage is associated with positive feedback loops between inflammatory processes and degenerative and autoimmune processes [95, 189]. Thus, CFS and ME show a similar pattern to other chronic degenerative disorders in which the initiating trigger is not well defined, for example, clinical depression, schizophrenia, multiple sclerosis, Parkinson's disease, inflammatory bowel disease, cancers, including breast cancer, and autoimmune disorders, lupus erythematosus, Sjögren's syndrome and rheumatoid arthritis, and so on. Moreover, patients with these disorders are primed to develop CF and CFS (and probably ME) through activated immunoinflammatory and O&NS pathways [12, 95]. For example, the prevalence of CF/CFS is very high in the above-mentioned autoimmune (41% to 81%) and inflammatory disorders, such as ankylosing spondylitis, biliary cirrhosis, post-poliomyelitis and psoriatic arthritis (48% to 50%) . In post-stroke patients, fatigue is associated with inflammatory biomarkers . Pascoe et al.  reviewed that post-stroke depression is caused by inflammatory and O&NS processes. By inference, similar processes may explain the onset of post-stroke fatigue. Research also showed a significant association between fatigue and cardiovascular disease (CVD), another inflammatory and O&NS disease . There is also an increased incidence of chronic fatigue in hemodialysis patients ('hemodialysis fatigue') . Since hemodialysis is accompanied by inflammatory and O&NS processes, the latter could also explain the increased incidence of fatigue during hemodialysis. In the postpartum period, another inflammatory state, increased levels of fatigue were found with a significant overlap between postnatal fatigue and depressive symptoms . IFNα-based immunotherapy not only causes clinical depression through induction of the cytokine network, but also by an increased incidence of fatigue and CFS-like symptoms [197, 198]. Increased bacterial translocation is also associated with the onset of ME/CFS . Loosening of the gut barrier may allow poorly invasive Gram-negative bacteria to translocate from the gut into the mesenteric lymph nodes and sometimes into the blood stream. Once translocated, the LPS is recognized by the Toll-like receptor 4 (TLR4) complex, which primes immune cells and consequently activates inflammatory and O&NS pathways [12, 199].
Psychological stressors are also associated with the onset of ME/CFS . Psychosocial stress also increases the frequency of relapses or a general worsening of symptoms . This may be explained by psychological stress leading to elevated levels of proinflammatory cytokines and O&NS processes that may well create the environment that fosters increased disease activity .
In contrast to sickness behavior, which is a CIRS response to infection/injury, a number of pathological predisposing factors may increase the vulnerability to develop ME/CFS. For example, IgG subclass deficiencies, vitamin D deficits, immune gene polymorphisms and a lowered ω3/ω6 PUFA ratio are observed in ME/CFS [12, 134]. IgG1 and IgG3 subclass deficiencies increase the risk to infections and autoimmune and inflammatory responses and thus to ME/CFS [12, 185]. A decrease in vitamin D is associated with ME/CFS, decreasing not only bone density, but also increasing the susceptibility to, and severity of, infections , in part via the regulation of NFκB . Genetic polymorphisms in TNFα, IFNγ, IL-17, IL-10 and HLA genes are associated with the onset of ME/CFS . The DISC1 gene is a susceptibility factor for ME/CFS, as well as for schizophrenia and depression . DISC1 has a significant role in early development, including in the regulation of neuronal migration . Given the relevance of altered mitochondrial function to ME/CFS, it is interesting that DISC1 is strongly associated with mitochondria, significantly regulating mitochondrial function and transport . A possible role of early life immune insult has been proposed for ME/CFS, suggesting that the immune system may be primed by prenatal and postnatal immune regulatory events for an altered response to infection . The lowered ω3/ω6 ratio detected in ME/CFS patients predisposes towards inflammatory and autoimmune responses as ω3 PUFAs are strongly anti-inflammatory and ω6 PUFAs proinflammatory .
Both sickness behavior and ME/CFS show a phenomenological overlap, both presenting with fatigue, malaise, hyperalgesia, sleepiness, neurocognitive symptoms and mood symptoms. Post-exertional malaise following mental and physical activities, a characteristic symptom of ME, probably also occurs during sickness behavior. While gastrointestinal symptoms are diagnostic criteria for some case definitions of ME/CFS, these symptoms are not typical for sickness behavior. Some typical sickness behavior symptoms, such as psychomotor retardation, anorexia and weight loss do not occur in ME/CFS unless there is comorbid depression. While pyrexia is a hallmark of acute inflammation, mild fever may occur in a few patients with ME/CFS. While sickness behavior is a short-lasting, adaptive and acute inflammatory state, ME/CFS is a chronic disorder characterized by a progressive or relapse-remitting course and with an extremely low recovery rate. While proinflammatory cytokines induce the beneficial sickness behavior response, ME/CFS is accompanied by chronic low-grade inflammation, O&NS, autoimmune responses, and wider immune alterations. Proinflammatory cytokines and Th1 cytokines and other inflammatory mediators together with elevated O&NS can induce a wide range of empirical abnormalities and disabling symptoms. These molecules conspire to create other differences between the acute sickness response, which is a state of proinflammatory cytokine-induced energy conservation, and ME/CFS, which is a chronic disease underpinned by a state of chronic energy depletion . In contrast to sickness behavior, which is a CIRS response to acute infection/injury, the initial trigger in ME/CFS is not always well defined and encompasses acute and chronic infections, multiple autoimmune and (neuro)inflammatory diseases and psychosocial stressors. In contrast to sickness behavior, some specific risk factors predispose to develop ME/CFS, for example, IgG deficiencies, immune gene polymorphisms and reduced ω3/ω6 PUFA ratio. While sickness behaviors are halted with the resolution of inflammation, ME/CFS is a chronic disorder associated with positive feedback loops between inflammatory and O&NS processes as well as degenerative and autoimmune processes. Table 1 and Figure 2 shows that sickness behavior and ME/CFS are two different conditions; that is, an adaptive beneficial response to proinflammatory cytokines on the one hand, and a chronic inflammation/O&NS-related disabling disorder on the other.
chronic fatigue syndrome
central nervous system
irritable bowel syndrome
IL-1 receptor antagonist
oxidative and nitrosative stress
post-exertion malaise lasting more than 24 h
polyunsaturated fatty acids
reactive nitrogen species
reactive oxygen species
36-item short-form health survey
sympathetic nervous system
transforming growth factor
tumor necrosis factor.
Hetem RS, Mitchell D, Maloney SK, Meyer LC, Fick LG, Kerley GI, Fuller A: Fever and sickness behavior during an opportunistic infection in a free-living antelope, the greater kudu (Tragelaphus strepsiceros). Am J Physiol Regul Integr Comp Physiol. 2008, 294: R246-R254.
Hart BL: Biological basis of the behavior of sick animals. Neurosci Biobehav Rev. 1988, 12: 123-137. 10.1016/S0149-7634(88)80004-6.
Maes M, Berk M, Goehler L, Song C, Anderson G, Gałecki P, Leonard B: Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med. 2012, 10: 66-10.1186/1741-7015-10-66.
Kluger MJ: The evolution and adaptive value of fever. Am Sci. 1978, 66: 38-43.
Maier SF, Watkins LR: Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev. 1998, 105: 83-107.
Wynne AM, Henry CJ, Godbout JP: Immune and behavioral consequences of microglial reactivity in the aged brain. Integr Comp Biol. 2009, 49: 254-266. 10.1093/icb/icp009.
Charlton BG: The malaise theory of depression: major depressive disorder is sickness behavior and antidepressants are analgesic. Med Hypotheses. 2000, 54: 126-130. 10.1054/mehy.1999.0986.
Komaroff AL, Fagioli LR, Doolittle TH, Gandek B, Gleit MA, Guerriero RT, Kornish RJ, Ware NC, Ware JE, Bates DW: Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. Am J Med. 1996, 101: 281-290. 10.1016/S0002-9343(96)00174-X.
Cairns R, Hotopf M: A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). 2005, 55: 20-31. 10.1093/occmed/kqi013.
Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S: Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011, 270: 327-338. 10.1111/j.1365-2796.2011.02428.x.
Maes M, Twisk FN, Johnson C: Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res. 2012, 200: 754-760. 10.1016/j.psychres.2012.03.031.
Morris G, Maes M: A neuro-immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metab Brain Dis.
Maes M, Twisk FN, Ringel K: Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. Psychother Psychosom. 2012, 81: 286-295. 10.1159/000336803.
Arnett SV, Clark IA: Inflammatory fatigue and sickness behaviour - lessons for the diagnosis and management of chronic fatigue syndrome. J Affect Disord. 2012, 141: 130-142. 10.1016/j.jad.2012.04.004.
Clark IA, Budd AC, Alleva LM: Sickness behaviour pushed too far--the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma. Malar J. 2008, 7: 208-10.1186/1475-2875-7-208.
Fukuda K, Straus SE, Hickie I, Sharpe M, Dobbins JG, Komaroff AL: The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med. 1994, 121: 953-959.
Maes M, Twisk FN: Chronic fatigue syndrome: Harvey and Wessely's (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med. 2010, 8: 35-10.1186/1741-7015-8-35.
Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI: Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chron Fatigue Syndr. 2003, 11: 7-36.
Maes M: "Functional" or "psychosomatic" symptoms, e.g. a flu-like malaise, aches and pain and fatigue, are major features of major and in particular of melancholic depression. Neuro Endocrinol Lett. 2009, 30: 564-573.
Anderson G, Maes M, Berk M: Biological underpinnings of the commonalities in depression, somatization, and chronic fatigue syndrome. Med Hypotheses. 2012, 78: 752-756. 10.1016/j.mehy.2012.02.023.
Skapinakis P, Lewis G, Mavreas V: Unexplained fatigue syndromes in a multinational primary care sample: specificity of definition and prevalence and distinctiveness from depression and generalized anxiety. Am J Psychiatry. 2003, 160: 785-787. 10.1176/appi.ajp.160.4.785.
Maes M: An intriguing and hitherto unexplained co-occurrence: depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways. Prog Neuropsychopharmacol Biol Psychiatry. 2011, 35: 784-794. 10.1016/j.pnpbp.2010.06.023.
Roy-Byrne P, Afari N, Ashton S, Fischer M, Goldberg J, Buchwald D: Chronic fatigue and anxiety/depression: a twin study. Br J Psychiatry. 2002, 180: 29-34. 10.1192/bjp.180.1.29.
Zachrisson O, Regland B, Jahreskog M, Kron M, Gottfries CG: A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J Psychosom Res. 2002, 52: 501-509. 10.1016/S0022-3999(01)00315-4.
Hawk C, Jason LA, Torres-Harding S: Differential diagnosis of chronic fatigue syndrome and major depressive disorder. Int J Behav Med. 2006, 13: 244-251. 10.1207/s15327558ijbm1303_8.
Anand AC, Kumar R, Rao MK, Dham SK: Low grade pyrexia: is it chronic fatigue syndrome?. J Assoc Physicians India. 1994, 42: , 606-608.
Camus F, Henzel D, Janowski M, Raguin G, Leport C, Vildé JL: Unexplained fever and chronic fatigue: abnormal circadian temperature pattern. Eur J Med. 1992, 1: 30-36.
Freeman R, Komaroff AL: Does the chronic fatigue syndrome involve the autonomic nervous system?. Am J Med. 1997, 102: 357-364. 10.1016/S0002-9343(97)00087-9.
Allen J, Murrary A, Di Maria C, Newton JL: Chronic fatigue syndrome and impaired peripheral pulse characteristics on orthostasis - a new potential diagnostic biomarker. Physiol Meas. 2010, 33: 231-241.
Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DEJ: Symptoms of autonomic dysfunction in chronic fatigue syndrome. Q J Med. 2007, 100: 519-526. 10.1093/qjmed/hcm057.
Winkler AS, Blair D, Marsden JT, Peters TJ, Wessely S, Cleare AJ: Autonomic function and serum erythropoietin levels in chronic fatigue syndrome. J Psychosom Res. 2004, 56: 179-183. 10.1016/S0022-3999(03)00543-9.
Montague TJ, Marrie TJ, Klassen GA, Bewick DJ, Horacek BM: Cardiac function at rest and with exercise in the chronic fatigue syndrome. Chest. 1989, 95: 779-784. 10.1378/chest.95.4.779.
Pagani M, Lucini D, Mela GS, Langewitz W, Malliani A: Sympathetic overactivity in subjects complaining of unexplained fatigue. Clin Sci (Lond). 1994, 87: 655-661.
De Becker P, Dendale P, De Meirleir K, Campine I, Vandenborne K, Hagers Y: Autonomic testing in patients with chronic fatigue syndrome. Am J Med. 1998, 105: 122S-126S.
Soetekouw PM, Lenders JW, Bleijenberg G, Thien T, van der Meer JW: Autonomic function in patients with chronic fatigue syndrome. Clin Auton Res. 1999, 9: 334-340. 10.1007/BF02318380.
Streeten DH, Anderson GH: The role of delayed orthostatic hypotension in the pathogenesis of chronic fatigue. Clin Auton Res. 1998, 8: 119-124. 10.1007/BF02267822.
Axelrod Axelrod FB, Chelimsky GG, Weese-Mayer DE: Pediatric autonomic disorders. Pediatrics. 2006, 118: 309-321. 10.1542/peds.2005-3032.
Stewart JM: Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res. 2000, 48: 218-226. 10.1203/00006450-200008000-00016.
Reynolds NL, Brown MM, Jason LA: The relationship of Fennell phases to symptoms among patients with chronic fatigue syndrome. Eval Health Prof. 2009, 32: 264-280. 10.1177/0163278709338558.
Wilson A, Hickie I, Lloyd A, Hadzi-Pavlovic D, Boughton C, Dwyer J, Wakefield D: Longitudinal study of outcome of chronic fatigue syndrome. Br Med J. 1994, 308: 756-759. 10.1136/bmj.308.6931.756.
Tiersky LA, DeLuca J, Hill N, Dhar SK, Johnson SK, Lange G, Rappolt G, Natelson BH: Longitudinal assessment of neuropsychological functioning, psychiatric status, functional disability and employment status in chronic fatigue syndrome. Appl Neuropsychol. 2001, 8: 41-50. 10.1207/S15324826AN0801_6.
Hill NF, Tiersky LA, Scavalla VR, Lavietes M, Natelson BH: Natural history of severe chronic fatigue syndrome. Arch Phys Med Rehabil. 1999, 80: 1090-1094. 10.1016/S0003-9993(99)90066-7.
Peterson PK, Schenck CH, Sherman R: Chronic fatigue syndrome in Minnesota. Minn Med. 1991, 74: 21-26.
Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ: Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci USA. 2008, 105: 17151-17156. 10.1073/pnas.0806682105.
Kerfoot SM, D'Mello C, Nguyen H, Ajuebor MN, Kubes P, Le T, Swain MG: TNF-alpha-secreting monocytes are recruited into the brain of cholestatic mice. Hepatology. 2006, 43: 154-162. 10.1002/hep.21003.
D'Mello C, Le T, Swain MG: Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci. 2009, 29: 2089-2102. 10.1523/JNEUROSCI.3567-08.2009.
Berk M, Berk L, Dodd S, Jacka FN, Fitzgerald PB, de Castella AR, Filia S, Filia K, Kulkarni J, Jackson HJ, Stafford L: Psychometric properties of a scale to measure investment in the sick role: the Illness Cognitions Scale. J Eval Clin Pract. 2012, 18: 360-364. 10.1111/j.1365-2753.2010.01570.x.
Peters A: The energy request of inflammation. Endocrinology. 2006, 147: 4550-4552. 10.1210/en.2006-0815.
Bosutti A, Malaponte G, Zanetti M, Castellino P, Heer M, Guarnieri G, Biolo G: Calorie restriction modulates inactivity-induced changes in the inflammatory markers C-reactive protein and pentraxin-3. J Clin Endocrinol Metab. 2008, 93: 3226-3229. 10.1210/jc.2007-1684.
MacDonald L, Radler M, Paolini AG, Kent S: Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias. Am J Physiol Regul Integr Comp Physiol. 2011, 301: R172-184. 10.1152/ajpregu.00057.2011.
Straub RH: Evolutionary medicine and chronic inflammatory state-known and new concepts in pathophysiology. J Mol Med (Berl). 2012, 90: 523-534. 10.1007/s00109-012-0861-8.
Kumar RK, Wakefield D: Inflammation: chronic. eLS. 2010, 10.1002/9780470015902.a0000944.pub3
Vermeulen RC, Kurk RM, Visser FC, Sluiter W, Scholte HR: Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med. 2010, 8: 93-10.1186/1479-5876-8-93.
Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ: Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radical Biol Med. 2005, 39: 584-589. 10.1016/j.freeradbiomed.2005.04.020.
Behan WM, More IA, Behan PO: Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol. 1991, 83: 61-65. 10.1007/BF00294431.
Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R: Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle. Neuromuscul Disord. 1998, 8: 204-209. 10.1016/S0960-8966(98)00021-2.
Myhill S, Booth NE, McLaren-Howard J: Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009, 2: 1-16.
Morris G, Maes M: Increased nuclear factor-κB and loss of p53 are key mechanisms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Hypotheses. 2012, 10: 66.
Paul L, Wood L, Behan WM, Maclaren WM: Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. Eur J Neurol. 1999, 6: 63-69. 10.1046/j.1468-1331.1999.610063.x.
Arnold DL, Bore PJ, Radda GK, Styles P, Taylor DJ: Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion/fatigue syndrome. Lancet. 1984, 323: 1367-1369. 10.1016/S0140-6736(84)91871-3.
Wong R, Lopaschuk G, Zhu G, Walker D, Catellier D, Burton D, Teo K, Collins-Nakai R, Montague T: Skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy. Chest. 1992, 102: 1716-1722. 10.1378/chest.102.6.1716.
Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ: Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. 2012, 25: 1073-1087. 10.1002/nbm.2772.
Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, Nestadt P, Levine SM, Mathew SJ, Shungu DC: Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. NMR Biomed. 2010, 23: 643-650. 10.1002/nbm.1512.
Fink MP: Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis?. Crit Care Clin. 2001, 17: 219-237. 10.1016/S0749-0704(05)70161-5.
Gottlieb E, Vander Heiden MG, Thompson CB: Bcl-xL prevents the initial decrease in mitochondrial membrane potential and subsequent reactive oxygen species production during tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol. 2000, 20: 5680-5689. 10.1128/MCB.20.15.5680-5689.2000.
Li C, Liu Q, Li N, Chen W, Wang L, Wang Y, Yu Y, Cao X: EAPF/Phafin-2, a novel endoplasmic reticulum-associated protein, facilitates TNF-alpha-triggered cellular apoptosis through endoplasmic reticulum-mitochondrial apoptotic pathway. J Mol Med (Berl). 2008, 86: 471-484. 10.1007/s00109-007-0298-7.
He Y, Leung KW, Zhang YH, Duan S, Zhong XF, Jiang RZ, Peng Z, Tombran-Tink J, Ge J: Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: protection by antioxidants. Invest Ophthalmol Vis Sci. 2008, 49: 1447-1458. 10.1167/iovs.07-1361.
Mahad DJ, Ziabreva I, Campbell G, Lax N, White K, Hanson PS, Lassmann H, Turnbull DM: Mitochondrial changes within axons in multiple sclerosis. Brain. 2009, 132: 1161-1174. 10.1093/brain/awp046.
Chakraborty S, Kaushik DK, Gupta M, Basu A: Inflammasome signaling at the heart of central nervous system pathology. J Neurosci Res. 2010, 88: 1615-1631.
Xie YW, Wolin MS: Role of nitric oxide and its interaction with superoxide in the suppression of cardiac muscle mitochondrial respiration. Involvement in response to hypoxia/reoxygenation. Circulation. 1996, 94: 2580-2586. 10.1161/01.CIR.94.10.2580.
Bossy-Wetzel E, Lipton SA: Nitric oxide signaling regulates mitochondrial number and function. Cell Death Differ. 2003, 10: 757-760. 10.1038/sj.cdd.4401244.
Brown GC, Borutaite V: Nitric oxide inhibition of mitochondrial respiration and its role in cell death. Free Radic Biol Med. 2002, 33: 1440-1450. 10.1016/S0891-5849(02)01112-7.
Brown GC, Borutaite V: Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta. 2004, 1658: 44-49. 10.1016/j.bbabio.2004.03.016.
Riobo NA, Clementi E, Melani M, Boveris A, Cadenas E, Moncada S, Poderoso JJ: Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through peroxynitrite formation. Biochem J. 2001, 359: 139-145. 10.1042/0264-6021:3590139.
Brown GC, Borutaite V: Nitric oxide and mitochondrial respiration in the heart. Cardiovasc Res. 2007, 75: 283-290. 10.1016/j.cardiores.2007.03.022.
Maes M, Mihaylova I, Bosmans E: Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. Neuro Endocrinol Lett. 2007, 28: 456-462.
Allen DG, Lamb GD, Westerbland H: Skeletal muscle fatigue: cellular mechanisms. Physiol Rev. 2008, 88: 287-332. 10.1152/physrev.00015.2007.
Booth NE, Myhill S, McLaren-Howard J: Mitochondrial dysfunction and the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Int J Clin Exp Med. 2012, 5: 208-220.
Atkin TA, MacAskill AF, Brandon NJ, Kittler JT: Disrupted in schizophrenia-1 regulates intracellular trafficking of mitochondria in neurons. Mol Psychiatry. 2011, 16: 122-124. 10.1038/mp.2010.110.
Viljoen M, Panzar A: Sickness behaviour: causes and effects. SA Fam Pract. 2004, 45: 15-18.
Marty V, El Hachmane M, Amedee T: Dual modulation of synaptic transmission in the nucleus tractus solitarius by prostaglandin E2 synthesized downstream of IL-1beta. Eur J Neurosci. 2008, 27: 3132-3150. 10.1111/j.1460-9568.2008.06296.x.
Bechmann I, Galea I, Perry VH: What is the blood-brain barrier (not)?. Trends Immunol. 2007, 28: 5-11. 10.1016/j.it.2006.11.007.
Quan N, Banks WA: Brain-immune communication pathways. Brain Behav Immun. 2007, 21: 727-735. 10.1016/j.bbi.2007.05.005.
Francis J, Chu Y, Johnson AK, Weiss RM, Felder RB: Acute myocardial infarction induces hypothalamic cytokine synthesis. Am J Physiol Heart Circ Physiol. 2004, 286: H2264-2271. 10.1152/ajpheart.01072.2003.
Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT: Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007, 55: 453-462. 10.1002/glia.20467.
Steinshamn S, Waage A: Lack of endotoxin tolerance with respect to TNF alpha production in the subarachnoid space. APMIS. 2000, 108: 107-112. 10.1034/j.1600-0463.2000.d01-33.x.
Banks WA, Kastin AJ, Broadwell RD: Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation. 1995, 2: 241-248. 10.1159/000097202.
Konsman JP, Luheshi GN, Bluthe RM, Dantzer R: The vagus nerve mediates behavioural depression, but not fever, in response to peripheral immune signals; a functional anatomical analysis. Eur J Neurosci. 2000, 12: 4434-4446. 10.1046/j.0953-816X.2000.01319.x.
Hwang SY, Jung JS, Kim TH, Lim SJ, Oh ES, Kim JY, Ji KA, Joe EH, Cho KH, Han IO: Ionizing radiation induces astrocyte gliosis through microglia activation. Neurobiol Dis. 2006, 21: 457-467. 10.1016/j.nbd.2005.08.006.
Kluger MJ, Rothenburg BA: Fever and reduced iron: their interaction as a host defense response to bacterial infection. Science. 1979, 203: 374-376. 10.1126/science.760197.
Eskandari F, Webster JI, Sternberg EM: Neural immune pathways and their connection to inflammatory diseases. Arthritis Res Ther. 2003, 5: 251-265. 10.1186/ar1002.
Tracey KJ: The inflammatory reflex. Nature. 2002, 420: 853-859. 10.1038/nature01321.
Ackerman KD, Felten SY, Bellinger DL, Felten DL: Noradrenergic sympathetic innervation of the spleen: III Development of innervation in the rat spleen. J Neurosci Res. 1987, 18: 49-54. 10.1002/jnr.490180109.
Maes M, Lin A, Kenis G, Egyed B, Bosmans E: The effects of noradrenaline and alpha-2 adrenoceptor agents on the production of monocytic products. Psychiatry Res. 2000, 96: 245-253. 10.1016/S0165-1781(00)00216-X.
Maes M, Twisk FN, Kubera M, Ringel K: Evidence for inflammation and activation of cell-mediated immunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J Affect Disord. 2012, 136: 933-939. 10.1016/j.jad.2011.09.004.
Heesen C, Nawrath L, Reich C, Bauer N, Schulz KH, Gold SM: Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour?. J Neurol Neurosurg Psychiatry. 2006, 77: 34-39. 10.1136/jnnp.2005.065805.
Ishikawa T, Kokura S, Sakamoto N, Okajima M, Matsuyama T, Sakai H, Okumura Y, Adachi S, Yoshida N, Uchiyama K, Handa O, Takagi T, Konishi H, Wakabayashi N, Yagi N, Ando T, Uno K, Naito Y, Yoshikawa T: Relationship between circulating cytokine levels and physical or psychological functioning in patients with advanced cancer. Clin Biochem. 2012, 45: 207-211. 10.1016/j.clinbiochem.2011.09.007.
Bower JE, Ganz PA, Aziz N, Fahey JL: Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med. 2002, 64: 604-611.
Robson-Ansley PJ, Smith LL: Causes of extreme fatigue in under performing athelethes - a synthesis of recent hypothesis and reviews. SAJSM. 2006, 18: 108-114.
Norheim KB, Harboe E, Goransson LG, Omdal R: Interleukin-1 inhibition and fatigue in primary Sjogren's syndrome--a double blind, randomised clinical trial. PLoS ONE. 2012, 7: e30123-10.1371/journal.pone.0030123.
Myers JS, Pierce J, Pazdernik T: Neurotoxicology of chemotherapy in relation to cytokine release, the blood-brain barrier, and cognitive impairment. Oncol Nurs Forum. 2008, 35: 916-920. 10.1188/08.ONF.916-920.
Dinarello CA: Biologic basis for interleukin-1 in disease. Blood. 1996, 87: 2095-2147.
Gemma C, Fister M, Hudson C, Bickford PC: Improvement of memory for context by inhibition of caspase-1 in aged rats. Eur J Neurosci. 2005, 22: 1751-1756. 10.1111/j.1460-9568.2005.04334.x.
Terrando N, Rei Fidalgo A, Vizcaychipi M, Cibelli M, Ma D, Monaco C, Feldmann M, Maze M: The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction. Crit Care. 2010, 14: R88-10.1186/cc9019.
Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW: Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun. 2008, 22: 301-311. 10.1016/j.bbi.2007.08.014.
Kent S, Bret-Dibat JL, Kelley KW, Dantzer R: Mechanisms of sickness-induced decreases in food-motivated behavior. Neurosci Biobehav Rev. 1996, 20: 171-175. 10.1016/0149-7634(95)00037-F.
Koo JW, Russo SJ, Ferguson D, Nestler EJ, Duman RS: Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci USA. 2010, 107: 2669-2674. 10.1073/pnas.0910658107.
Avitsur R, Yirmiya R: Cytokines inhibit sexual behavior in female rats: I. Synergistic effects of tumor necrosis factor alpha and interleukin-1. Brain Behav Immun. 1999, 13: 14-32. 10.1006/brbi.1999.0555.
Garcia-Ruiz C, Colell A, Mari M, Morales A, Fernandez-Checa JC: Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species, role of mitochondrial glutathione. J Biol Chem. 1997, 272: 11369-11377. 10.1074/jbc.272.17.11369.
Morgan D, Oliveira-Emilio HR, Keane D, Hirata AE, Santos da Rocha M, Bordin S, Curi R, Newsholme P, Carpinelli AR: Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line. Diabetologia. 2007, 50: 359-369. 10.1007/s00125-006-0462-6.
Merali Z, Lacosta S, Anisman H: Effects of interleukin-1beta and mild stress on alterations of norepinephrine, dopamine and serotonin neurotransmission: a regional microdialysis study. Brain Res. 1997, 761: 225-235. 10.1016/S0006-8993(97)00312-0.
Korkmaz A, Oter S, Seyrek M, Topal T: Molecular, genetic and epigenetic pathways of peroxynitrite-induced cellular toxicity. Interdiscip Toxicol. 2009, 2: 219-228.
Glund S, Deshmukh A, Long YC, Moller T, Koistinen HA, Caidahl K, Zierath JR, Krook A: Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle. Diabetes. 2007, 56: 1630-1637. 10.2337/db06-1733.
Patarca R: Pteridines and neuroimmune function and pathology. J Chron Fatigue Syndr. 1997, 3: 69-86.
Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D: Neopterin production, tryptophan degradation, and mental depression--what is the link?. Brain Behav Immun. 2002, 16: 590-595. 10.1016/S0889-1591(02)00006-5.
Bellmann-Weiler R, Schroecksnadel K, Holzer C, Larcher C, Fuchs D, Weiss G: IFN-gamma mediated pathways in patients with fatigue and chronic active Epstein Barr virus-infection. J Affect Disord. 2008, 108: 171-176. 10.1016/j.jad.2007.09.005.
Brenu EW, van Driel ML, Staines DR, Ashton KJ, Hardcastle SL, Keane J, Tajouri L, Peterson D, Ramos SB, Marshall-Gradisnik SM: Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2012, 10: 88-10.1186/1479-5876-10-88.
Chesnokova V, Melmed S: Minireview: neuro-immuno-endocrine modulation of the hypothalamic-pituitary-adrenal (HPA) axis by gp130 signaling molecules. Endocrinology. 2002, 143: 1571-1574. 10.1210/en.143.5.1571.
Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, Keane J, Klimas NG, Marshall-Gradisnik SM: Immunological abnormalities as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2011, 9: 81-10.1186/1479-5876-9-81.
Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, Broderick G, Klimas NG: Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS ONE. 2010, 5: e10817-10.1371/journal.pone.0010817.
Mihaylova I, DeRuyter M, Rummens JL, Bosmans E, Maes M: Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells. Neuro Endocrinol Lett. 2008, 28: 477-483.
Klimas N, Salvato F, Morgan R, Fletcher MA: Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol. 1990, 28: 1403-1410.
Vaziri ND: Causal link between oxidative stress, inflammation, and hypertension. Iran J Kidney Dis. 2008, 2: 1-10.
Murr C, Fuchs D, Gossler W, Hausen A, Reibnegger G, Werner ER, Werner-Felmayer G, Esterbauer H, Wachter H: Enhancement of hydrogen peroxide-induced luminol-dependent chemiluminescence by neopterin depends on the presence of iron chelator complexes. FEBS Lett. 1994, 338: 223-226. 10.1016/0014-5793(94)80369-2.
Murayama R, Kobayashi M, Takeshita A, Yasui T, Yamamoto M: MAPKs, activator protein-1 and nuclear factor-κB mediate production of interleukin-1β-stimulated cytokines, prostaglandin E2 and MMP-1 in human periodontal ligament cells. J Periodontal Res. 2011, 46: 568-575.
Maes M, Mihaylova I, Leunis JC: Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett. 2006, 27: 615-621.
Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E: Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009, 30: 470-476.
Miwa K, Fujita M: Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome. Heart Vessels. 2010, 25: 319-323. 10.1007/s00380-009-1206-6.
Jammes Y, Steinberg JG, Delliaux S: Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins. J Intern Med. 2011, 272: 74-84.
Fulle S, Pietrangelo T, Mancinelli R, Saggini R, Fano G: Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis. J Muscle Res Cell Motil. 2007, 28: 355-362. 10.1007/s10974-008-9128-y.
Maes M, Mihaylova I, Kubera M, Bosmans E: Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome. Neuro Endocrinol Lett. 2007, 28: 463-469.
Milczarek R, Hallmann A, Sokołowska E, Kaletha K, Klimek J: Melatonin enhances antioxidant action of alpha-tocopherol and ascorbate against NADPH- and iron-dependent lipid peroxidation in human placental mitochondria. J Pineal Res. 2010, 49: 149-155.
Ochoa JJ, Díaz-Castro J, Kajarabille N, García C, Guisado IM, De Teresa C, Guisado R: Melatonin supplementation ameliorates oxidative stress and inflammatory signaling induced by strenuous exercise in adult human males. J Pineal Res. 2011, 51: 373-380. 10.1111/j.1600-079X.2011.00899.x.
Maes M, Mihaylova I, Leunis JC: In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation. Neuro Endocrinol Lett. 2005, 26: 745-751.
Calder PC: Polyunsaturated fatty acids and inflammatory processes: New twists in an old tale. Biochimie. 2009, 91: 791-795. 10.1016/j.biochi.2009.01.008.
Esterbauer H, Schaur RJ, Zollner H: Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991, 11: 81-128. 10.1016/0891-5849(91)90192-6.
Kumar P, Kale RK, Baquer NZ: Estradiol modulates membrane-linked ATPases, antioxidant enzymes, membrane fluidity, lipid peroxidation, and lipofuscin in aged rat liver. J Aging Res. 2011, 2011: 580245.
Garcia JJ, Pinol-Ripoll G, Martinez-Ballarn E, Fuentes-Broto L, Miana-Mena FJ, Venegas C, Caballero B, Escames G, Coto-Montes A, Acuña-Castroviejo D: Melatonin reduces membrane rigidity and oxidative damage in the brain of SAMP(8) mice. Neurobiol Aging. 2011, 32: 2045-2054. 10.1016/j.neurobiolaging.2009.12.013.
Nava F, Carta G: Melatonin reduces anxiety induced by lipopolysaccharide in the rat. Neurosci Lett. 2001, 307: 57-60. 10.1016/S0304-3940(01)01930-9.
Chang CC, Tien CH, Lee EJ, Juan WS, Chen YH, Hung YC, Chen TY, Chen HY, Wu TS: Melatonin inhibits matrix metalloproteinase-9 (MMP-9) activation in the lipopolysaccharide (LPS)-stimulated RAW 264.7 and BV2 cells and a mouse model of meningitis. J Pineal Res. 2012, 53: 188-197. 10.1111/j.1600-079X.2012.00986.x.
Boullerne A, Petry KG, Geffard M: Circulating antibodies directed against conjugated fatty acids in sera of patients with multiple sclerosis. J Neuroimmunol. 1996, 65: 75-81. 10.1016/0165-5728(96)00010-0.
Hokama Y, Camproa CE, Hara C, Higa N, Siu N, Lau R, Kuribayashi T, Yabusaki K: Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic Ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins. J Clin Lab Anal. 2008, 22: 99-105. 10.1002/jcla.20217.
Hokama Y, Camproa CE, Hara C, Kuribayashi T, Le Huynh D, Yabusaki K: Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome. J Clin Lab Anal. 2009, 23: 210-212. 10.1002/jcla.20325.
Buchwald MD, Wener MH, Komaroff AL: Antineuronal antibody levels in chronic fatigue syndrome patients with neurologic abnormalities. 1991, 34: 1485-1486.
Bassi N, Amital D, Amital H, Doria A, Shoenfeld Y: Chronic fatigue syndrome: characteristics and possible causes for its pathogenesis. Isr Med Assoc J. 2008, 10: 79-82.
Nishikai M: Antinuclear antibodies in patients with chronic fatigue syndrome. Nippon Rinsho. 2007, 65: 1067-1070.
Klein R, Berg PA: High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: evidence for a clinical entity of both disorders. Eur J Med Res. 1995, 1: 21-26.
Tanaka S, Kuratsune H, Hidaka Y, Hakariya Y, Tatsumi KI, Takano T, Kanakura Y, Amino N: Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med. 2003, 12: 225-230.
Mostafa GA, Ibrahim DH, Shehab AA, Mohammed AK: The role of measurement of serum autoantibodies in prediction of pediatric neuropsychiatric systemic lupus erythematosus. J Neuroimmunol. 2010, 227: 195-201. 10.1016/j.jneuroim.2010.07.014.
Kato T, Hatanaka K: Purification of gangliosides by liquid-liquid partition chromatography. J Lipid Res. 2008, 49: 2474-2478. 10.1194/jlr.D800033-JLR200.
Adelman JS, Bentley GE, Wingfield JC, Martin LB, Hau M: Population differences in fever and sickness behaviors in a wild passerine: a role for cytokines. J Exp Biol. 2010, 213: 4099-4109. 10.1242/jeb.049528.
Hains LE, Loram LC, Taylor FR, Strand KA, Wieseler JL, Barrientos RM, Young JJ, Frank MG, Sobesky J, Martin TJ, Eisenach JC, Maier SF, Johnson JD, Fleshner M, Watkins LR: Prior laparotomy or corticosterone potentiates lipopolysaccharide-induced fever and sickness behaviors. J Neuroimmunol. 2011, 239: 53-60. 10.1016/j.jneuroim.2011.08.011.
Besedovsky H, del Rey A, Sorkin E, Dinarello CA: Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986, 233: 652-654. 10.1126/science.3014662.
Dunn AJ: Systemic interleukin-1 administration stimulates hypothalamic norepinephrine metabolism parallelling the increased plasma corticosterone. Life Sci. 1988, 43: 429-435. 10.1016/0024-3205(88)90522-X.
Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ: The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003, 9: 125-134.
Necela BM, Cidlowski JA: Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc Am Thorac Soc. 2004, 1: 239-246. 10.1513/pats.200402-005MS.
Turan T, Izgi HB, Ozsoy S, Tanrıverdi F, Basturk M, Asdemir A, Beşirli A, Esel E, Sofuoglu S: The effects of galantamine hydrobromide treatment on dehydroepiandrosterone sulfate and cortisol levels in patients with chronic fatigue syndrome. Psychiatry Investig. 2009, 6: 204-210. 10.4306/pi.2009.6.3.204.
Scott LV, Dinan TG: Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers. J Affect Disord. 1998, 47: 49-54. 10.1016/S0165-0327(97)00101-8.
Papadopoulos AS, Cleare AJ: Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol. 2011, 8: 22-32. 10.1038/nrendo.2011.153.
Tak LM, Cleare AJ, Ormel J, Manoharan A, Kok IC, Wessely S, Rosmalen JG: Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. Biol Psychol. 2011, 87: 183-194. 10.1016/j.biopsycho.2011.02.002.
Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, Chrousos GP, Gold PW: Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991, 73: 1224-1234. 10.1210/jcem-73-6-1224.
Scott LV, Medbak S, Dinan TG: Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome. Acta Psychiatr Scand. 1998, 97: 450-457. 10.1111/j.1600-0447.1998.tb10030.x.
Scott LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG: Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology. 1999, 24: 759-768. 10.1016/S0306-4530(99)00028-1.
Jerjes WK, Taylor NF, Wood PJ, Cleare AJ: Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome. Psychoneuroendocrinology. 2007, 32: 192-198. 10.1016/j.psyneuen.2006.12.005.
Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, Nagelkerken L: Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors. J Investig Med. 2001, 49: 195-204. 10.2310/6650.2001.34047.
Mastorakos G, Chrousos GP, Weber JS: Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab. 1993, 77: 1690-1694. 10.1210/jc.77.6.1690.
Jaattela M, Ilvesmaki V, Voutilainen R, Stenman UH, Saksela E: Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells. Endocrinology. 1991, 128: 623-639. 10.1210/endo-128-1-623.
Zhu Q, Solomon S: Isolation and mode of action of rabbit corticostatic (antiadrenocorticotropin) peptides. Endocrinology. 1992, 130: 1413-1423. 10.1210/en.130.3.1413.
Harden LM, du Plessis I, Poole S, Laburn HP: Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior. Physiol Behav. 2006, 89: 146-155. 10.1016/j.physbeh.2006.05.016.
Carlton ED, Demas GE, French SS: Leptin, a neuroendocrine mediator of immune responses, inflammation, and sickness behaviors. Horm Behav. 2012, 62: 272-279. 10.1016/j.yhbeh.2012.04.010.
Sherry CL, Kramer JM, York JM, Freund GG: Behavioral recovery from acute hypoxia is reliant on leptin. Brain Behav Immun. 2009, 23: 169-175. 10.1016/j.bbi.2008.09.011.
Lawrence CB, Brough D, Knight EM: Obese mice exhibit an altered behavioural and inflammatory response to lipopolysaccharide. Dis Model Mech. 2012, 5: 649-659. 10.1242/dmm.009068.
Cleare AJ, O'Keane V, Miell J: Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion. Clin Endocrinol (Oxf). 2001, 55: 113-119. 10.1046/j.1365-2265.2001.01341.x.
Pasco JA, Jacka FN, Williams LJ, Henry MJ, Nicholson GC, Kotowicz MA, Berk M: Leptin in depressed women: cross-sectional and longitudinal data from an epidemiologic study. J Affect Disord. 2008, 107: 221-225. 10.1016/j.jad.2007.07.024.
Beccano-Kelly D, Harvey J: Leptin: a novel therapeutic target in Alzheimer's disease?. Int J Alzheimers Dis. 2012, 2012: 594137.
Farooqui AA, Farooqui T, Panza F, Frisardi V: Metabolic syndrome as a risk factor for neurological disorders. Cell Mol Life Sci. 2012, 69: 741-762. 10.1007/s00018-011-0840-1.
Maloney EM, Boneva RS, Lin JM, Reeves WC: Chronic fatigue syndrome is associated with metabolic syndrome: results from a case-control study in Georgia. Metabolism. 2010, 59: 1351-1357. 10.1016/j.metabol.2009.12.019.
Roubenoff R, Roubenoff RA, Cannon JG, Kehayias JJ, Zhuang H, Dawson-Hughes B, Dinarello CA, Rosenberg IH: Rheumatoid cachexia: cytokine driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest. 1994, 93: 2379-2386. 10.1172/JCI117244.
Medzhitov R: Inflammation 2010: new adventures of an old flame. Cell. 2010, 140: 771-776. 10.1016/j.cell.2010.03.006.
Naess H, Sundal E, Myhr KM, Nyland HI: Postinfectious and chronic fatigue syndromes: clinical experience from a tertiary-referral centre in Norway. In Vivo. 2010, 24: 185-188.
Strickland PS, Levine PH, Peterson DL, O'Brien K, Fears T: Neuromyasthenia and chronic fatigue syndrome (CFS) in Northern Nevada/California: a ten-year follow-up of an outbreak. J Chron Fatigue Syndr. 2001, 9: 3-14.
Maes M: Inflammatory, and oxidative and nitrosative stress cascades as new drug targets in myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Modern Trends in Pharmacopsychiatry - Inflammation in Psychiatry. Edited by: Leonard B, Halaris A. Basel. Switzerland: S. Karger AG.
Nicolson GL, Nicolson NL, Haier J: Chronic fatigue syndrome patients subsequently diagnosed with Lyme disease Borrelia burgdorferi: evidence for mycoplasma species co-infections. J Chron Fatigue Syndr. 2008, 14: 5-17. 10.1080/10573320802091809.
Chia JK, Chia AY: Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol. 2008, 61: 43-48.
Hilgers A, Frank J: Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes. Wien Med Wochenschr. 1994, 144: 399-406.
Nicolson GL, Gan R, Haier J: Multiple co-infections (Mycoplasma, Chlamydia, human herpesvirus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS. 2003, 111: 557-566. 10.1034/j.1600-0463.2003.1110504.x.
Goudsmit EM, Howes S: Pacing to manage chronic fatigue syndrome Pacing: an additional strategy to manage fatigue in chronic fatigue syndrome. [http://freespace.virgin.net/david.axford/pacing.htm]
Kerr JR, Gough J, Richards SC, Main J, Enlander D, McCreary M, Komaroff AL, Chia JK: Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Gen Virol. 2010, 91: 893-897. 10.1099/vir.0.017590-0.
Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA: A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010, 24: 1209-1217. 10.1016/j.bbi.2010.04.012.
Zhang L, Gough J, Christmas D, Mattey DL, Richards SC, Main J, Enlander D, Honeybourne D, Ayres JG, Nutt DJ, Kerr JR: Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis. J Clin Pathol. 2010, 63: 56-164.
van Langenberg DR, Gibson PR: Systematic review: fatigue in inflammatory bowel disease. Aliment Pharmacol Ther. 2010, 32: 131-143. 10.1111/j.1365-2036.2010.04347.x.
McKechnie F, Lewis S, Mead G: A pilot observational study of the association between fatigue after stroke and C-reactive protein. J R Coll Physicians Edinb. 2010, 40: 9-12. 10.4997/JRCPE.2010.103.
Pascoe MC, Crewther SG, Carey LM, Crewther DP: Inflammation and depression: why poststroke depression may be the norm and not the exception. Int J Stroke. 2011, 6: 128-135. 10.1111/j.1747-4949.2010.00565.x.
Fitzpatrick AL, Reed T, Goldberg J, Buchwald D: The association between prolonged fatigue and cardiovascular disease in World War II veteran twins. Twin Res. 2004, 7: 571-577.
Sakkas GK, Karatzaferi C: Hemodialysis fatigue: just "simple" fatigue or a syndrome on its own right?. Front Physiol. 2012, 3: 306.
Kuo SY, Yang YL, Kuo PC, Tseng CM, Tzeng YL: Trajectories of depressive symptoms and fatigue among postpartum women. J Obstet Gynecol Neonatal Nurs. 2012, 41: 216-226. 10.1111/j.1552-6909.2011.01331.x.
Wichers MC, Kenis G, Koek GH, Robaeys G, Nicolson NA, Maes M: Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res. 2007, 62: 207-214. 10.1016/j.jpsychores.2006.09.007.
Nashan D, Reuter K, Mohr P, Agarwala SS: Understanding and managing interferon-α-related fatigue in patients with melanoma. Melanoma Res. 2012, 22: 415-423. 10.1097/CMR.0b013e328358d98c.
Maes M, Leunis JC: Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from Gram-negative bacteria. Neuro Endocrinol Lett. 2008, 29: 902-910.
Kang HK, Natelson BH, Mahan CM, Lee KY, Murphy FM: Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: a population-based survey of 30,000 veterans. Am J Epidemiol. 2003, 57: 141-148.
Maes M, Van Bockstaele DR, Gastel A, Song C, Schotte C, Neels H, DeMeester I, Scharpe S, Janca A: The effects of psychological stress on leukocyte subset distribution in humans: evidence of immune activation. Neuropsychobiology. 1999, 39: 1-9. 10.1159/000026552.
Berkovitz S, Ambler G, Jenkins M, Thurgood S: Serum 25-hydroxy vitamin D levels in chronic fatigue syndrome: a retrospective survey. Int J Vitam Nutr Res. 2009, 79: 250-254. 10.1024/0300-98126.96.36.199.
Chen Y, Kong J, Sun T, Li G, Szeto FL, Liu W, Deb DK, Wang Y, Zhao Q, Thadhani R, Li YC: 1,25-Dihydroxyvitamin D3 suppresses inflammation-induced expression of plasminogen activator inhibitor-1 by blocking nuclear factor-κB activation. Arch Biochem Biophys. 2011, 507: 241-247. 10.1016/j.abb.2010.12.020.
Fukuda S, Hashimoto R, Ohi K, Yamaguti K, Nakatomi Y, Yasuda Y, Kamino K, Takeda M, Tajima S, Kuratsune H, Nishizawa Y, Watanabe Y: A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome. Life Sci. 2010, 86: 722-725. 10.1016/j.lfs.2010.03.007.
Young-Pearse TL, Suth S, Luth ES, Sawa A, Selkoe DJ: Biochemical and functional interaction of DISC1 and APP regulates neuronal migration during mammalian cortical development. Neurosci. 2010, 30: 10431-10440. 10.1523/JNEUROSCI.1445-10.2010.
Dietert RR, Dietert JM: Possible role for early-life immune insult including developmental immunotoxicity in chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME). Toxicology. 2008, 247: 61-72. 10.1016/j.tox.2008.01.022.
The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/11/64/prepub
No specific funding was obtained for this specific review. MB has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, Mayne Pharma and Servier, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvayand Wyeth, and served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck and Servier. The other authors declare that they have no competing interests.
GM and MM participated in the design of this review, while all authors helped to draft the paper. All authors contributed equally to this paper. All authors read and approved the final version.
About this article
Cite this article
Morris, G., Anderson, G., Galecki, P. et al. A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior. BMC Med 11, 64 (2013). https://doi.org/10.1186/1741-7015-11-64
- chronic fatigue
- oxidative stress
- sickness behavior