Chronic fatigue syndrome (CFS) is a protracted illness that may follow an infectious diseases in a subset of patients and is characterized by clinically unexplained fatigue of at least 6 months duration that is not the result of ongoing exertion, is not substantially alleviated by rest, and results in substantial reduction in previous levels of occupational, educational, social, or personal activities (Fukuda et al., 1994). To make the diagnosis of CFS, the fatigue must be accompanied by at least four of the following eight self-reported symptoms: unusual post-exertion malaise; unrefreshing sleep; impaired short-term memory or concentration; headaches of a new type, pattern, or severity; muscle pain; multijoint pain without swelling or redness; sore throat; and tender cervical or axillary lymph nodes.
While fatigue as a symptom in general is very common, chronic fatigue syndrome itself is not but, where present, accounts for marked functional impairment and educational disruption, among especially adolescents. Yet many epidemiological associations seen in specialist clinics are absent in community cases of CFS. Because of the aforementioned symptom-complex hallmark of CFS, since the 1980s many unsuccessful attempts have been made to explain CFS on the basis of ongoing infection.
Neuroendocrine system changes in CFS, particularly in the hypothalamic–pituitary–adrenal (HPA) axis, are proposed, based on similarity of symptoms to those seen in glucocorticoid deficiency states.[1] Demitrack et al. found reduced basal evening glucocorticoid levels and increased basal evening ACTH concentrations, and low 24-h urinary-free cortisol excretion. CFS subjects also demonstrate a diminished maximal response to administration of ACTH and attenuated ACTH response to ovine corticotrophin-releasing hormone (CRH) administration. Subsequent reviews and studies addressing the HPA axis show conflicting results.[2] More recently, autonomic nervous system (ANS) responses that are closely linked to HPA function have come under scrutiny.[3] The HPA axis remains important also because of its role in control of immune response to infection and to behavioural and physiological responses in general.[4] Such activation of the HPA axis during infection or stress begins with release of CRH in both the central nervous system (CNS) and in peripheral tissues.
One of the best-studied examples of a post-infection fatigue syndrome is the illness following infectious mononucleosis.[5] To meet acute post-infection criteria during infectious mononucleosis convalescence, patients must have physical fatigue for at least two weeks with at least two of five associated symptoms of: hypersomnia, poor concentration, psycho-motor retardation, irritability, or anhedonia; in the setting of significant incapacity but devoid of any co-morbid psychiatric disorder. Further evaluation may also identify those who meet the CFS definition criteria even beyond six months post infection.
More recently, Hickie et al. (2006) developed criteria for a post-infectious fatigue following any of acute EBV mononucleosis, acute Ross River virus, and acute Q-fever (Coxiella burnetii) infections, criteria that also fulfill diagnostic criteria for CFS. Evaluations of such post-infectious mononucleosis patients by Cameron et al. (2006) and Vernon et al. (2006), however, failed to identify unusual persistence of the virus nor diagnostic changes in immune function. Expert consensus therefore remains that CFS stems from responses to prior infection and not to ongoing viral or immunologic factors.
CFS is not Ongoing Infection: But what is it?
The innate immune system is composed of circulating or cell-associated proteins encoded by genes that do not undergo programmed rearrangements and that do not require prior exposure to cognate ligands for expression. This system consists of antimicrobial products—cathelicidins and defensins—found in epithelial and phagocytic cells, the complement system, cytokines, natural killer cells, microglia cells in the CNS, and subsequent phagocytic cell ingestion and killing of micro-organisms. The cell-surface interaction of mononuclear cells and some epithelial cells with their respective target molecules is mediated by toll-like receptors (TLR) that bind to structurally conserved features on microbes, such as lipopolysaccharides and peptidoglycans and to cell proteins, and are known as pathogen-associated molecular patterns. Activation of each of the individual components and their downstream counterparts by exposure to “non-self” or “absence of self” leads to release of molecules that participate in control of infection or other non-self targets via inflammation and illness production through stimulation of the sickness response.[6] More recently, Matzinger (2002) proposed a “danger model” in which specific recognition of foreign proteins (those ‘‘non-self’’ or ‘‘altered self’ proteins’) is not driving the host response to infection or injury. Rather, it is recognition of the insult as ‘‘danger’’ that triggers the collective host responses. The danger system utilizes the components of both the innate and adaptive immune systems. Exposure of tissue antigen presenting cells to endogenous or to non-foreign “alarm signals”—be they DNA or RNA, heat shock proteins, or cytokines— released or generated as a result of injury, constitutes a “damage” control system. In the “danger” response concept, altered self occurs as a consequence of injury or exposure to endogenous substances that are usually sequestered. The involved tissue apparently dictates the level and type of subsequent immune response. In all of these views, the immune response is triggered by foreign molecules, altered self, or by “damage,” and is amplified by a cascade of inflammatory and metabolic events.
Craig (2002) and Mayer et al. (2006) reviewed the purported process of interoception, a self-sensing of the body’s level of functioning, as transmitted through small-calibre sensory, so-labelled “homeostatic”, afferents. Critchley et al. (2004) and Critchley (2005) suggest a composite of autonomic, affective, and cognitive factors to describe neural pathways underlying this awareness of complex bodily functions. Brain imaging during somatic stimuli have mapped in detail ascending and descending pathways associated with self-monitoring, their subsequent re-representation in the insular cortex, and afferent signaling, particularly through the autonomic nervous system. Just as there are anatomical areas associated with interoception, Northoff and Bermpohl (2004) identified anatomic components of the self in the brain and identified several cortical midline structures composing an anatomical unit, as well as lateral structures such as the right prefrontal and parietal cortices. The midline components include orbital and adjacent medial prefrontal cortex, the anterior cingulate cortex, the dorsomedial prefrontal cortex, and the posterior cingulate cortex. Rosenkranz et al. (2005), for instance, using functional magnetic resonance imaging, found changes in activation in the anterior cingulate cortex and the left insular cortex in patients with exacerbations of asthma: activity in the anterior cingulate cortex and insula was associated with markers of inflammation and airway obstruction in asthmatic subjects exposed to antigen. More recently, Vollmer-Conna et al. (2006) introduced the concept of “interoceptive profile” in reference to CFS subjects.
Adding to the texture of the analysis, the analytic philosopher, Patricia Churchland, emphasises the necessity of brain self-representation for the organism’s real-time ability to respond most appropriately to its environment. Further, philosopher, neuroscientist, and psychiatrist, Georg Northoff (2004), investigates how the brain indeed constructs subjective phenomena, including those concepts of self, consciousness, and emotion.[7] Beyond mapping the neural networks underlying interoception, exploration of an extended altered self-model in chronic sickness, including that of CFS and post-infectious fatigue, requires an audit of possible ‘‘self-representation” receptors; including non-self / altered self-products or immune / inflammatory system products, brain microglia, neurohormonal systems, etc.[8]
For their post-infectious fatigue patients, exercise physiologists recommend an exercise-to-tolerance (or just beyond and no more) approach, as overtraining has been associated with autonomic dysfunction, affecting both the adaptive sympathetic stress response, and the parasympathetic neuroendocrine system. Likewise, exertional hypotension and positive tilt-table tests are common manifestations of CFS.
Hormonal manifestations of CFS are to be anticipated, given the suspected role of stress as a precipitant of both over-training and CFS, and the close connection between the neurohypophysis and the pituitary-adrenal axis. Although a moderate level of stress enhances adrenal function, atrophy of the adrenal gland can result from excessive physical or psychological stress. Dysfunction of the hypothalamic-pituitary-adrenal (HPA)axis may result from a disturbance of serotonergic neurotransmission, with alterations in the neurally-induced activity of arginine vasopressin. Some of the symptoms of CFS—such as mental confusion, exertional malaise, weight changes and joint pain—are also seen in the syndrome of inappropriate anti-diuretic hormone (SIADH) release. Such inappropriate release of, or a sensitivity to, arginine vasopressin could contribute to CFS. Cortisol concentrations for those with established CFS are commonly reduced rather than increased. There may also be a reduced response of adrenocorticotropin, epinephrine, prolactin, and thyrotropin in response to a standard exercise, and these could contribute to the fatigue and weakness that characterize CFS.
Enigmatic medical conditions of hyperactive immune responses, with overlapping symptom-complexes, have recently been described: siliconosis, Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF), and post-vaccination phenomena. Immune mediated conditions—the autoimmune (AI) and auto-inflammatory diseases (AIFD)—are a leading cause of global morbidity and mortality. Such geo-epidemiological changes reflect a complex of genetic and environmental factors: a genetically susceptible person may develop an autoimmune or auto-inflammatory disease following exposure to a certain environmental factor. Infections, toxins, and drugs are linked not only with occurrence of immune-mediated conditions (causative) but also with their clinical manifestations (provocative). Such environmental factors with inherent immune adjuvant effects—i.e. silicone, alum, pristane, infectious components—are the sole inducers of autoimmunity in different animal models and likely provoke AI and AIFD in humans, including the four aforementioned hyperimmune syndromes. Formerly, such adjuvants were thought to pose little or no independent threat. In this context, the most studied adjuvant is tetramethylpentadecane (TMPD) or pristane, capable of inducing disease in a murine model of systemic lupus erythematosus (SLE). Much as in human disease, so in this model, autoantibody production and renal damage depend on type I interferon (IFN-I). Immunisation of animals with pristane accelerates production of IFN-I by monocytes via signalling through toll-like receptor 7 (TLR-7) and the cytoplasmic adapter protein MyD88. Immunization with another adjuvant, squalene, induce arthritis in rats and the production of SLE-associated autoantibodies in mice. The adjuvant aluminium may be contained in immune complexes produced following vaccination.
The manifold associations between infectious agents and autoimmunity or auto-inflammation has been established and possible mechanisms identified—i.e. molecular mimicry, epitope spreading, polyclonal activation, and others. Yet, several questions regarding the interaction between infections and autoimmunity remain to be elucidated. For instance, unlike the classical example of a one-to-one alliance between streptococcal infection and rheumatic fever, the association of several infectious agents with a single autoimmune disease has recently been described although, almost a century ago, Jules Freund developed the complete water-and-oil emulsion with killed mycobacteria adjuvant, or Freund’s adjuvant (CFA), shown to induce disease in many experimental models. Immunization of animals with thyroid antigen (thyroglobulin) and incomplete Freund’s adjuvant, lacking the mycobacterial component, induces only the production of anti-thyroid antibody. But immunisation with the same antigen joined to CFA results in antibody production and inflammatory lesions in the thyroid.
One of modern medicine’s greatest achievements, yet nevertheless on rare occasions, and not unlike infectious agents themselves, vaccines can induce the appearances of autoantibodies, inflammatory conditions, and overt autoimmune disease. In such cases, non-specific manifestations such as arthritis, neuronal damage, fatigue, encephalitis, and vasculitis are frequently described. These rare events and case-reports and post-marketing surveillance detect such adverse events weeks and even months or years following vaccination, leaving it difficult if not impossible to prove a causal relationship. For some vaccines, nevertheless, such a causal link was noted; a 1976 outbreak of Guillain-Barré syndrome (GBS) following immunization with “swine-flu” vaccine, for instance. Causal relationships have also been accepted for transverse myelitis following oral polio vaccine, arthritis following diphtheria-tetanus-pertussis (DTP), and autoimmune thrombocytopenia after measles-mumps-rubella (MMR) vaccination (and now also with the mRNA-based CoVid-19 vaccines). A number of animal models support these inferences: immunisation of puppies and production of various autoantibodies including lupus-associated ones; vaccination protocols of diabetic prone newborn animals associated with increased incidence of diabetes; intra-peritoneal immunisation of Salmon fish with oil-adjuvanted vaccines resulted in the production of anti-nuclear, anti-b2GPI, anti-ferritin, and anti-salmon blood extracts antibodies, as well as autoimmune granulomatous diseases of the liver and peritoneum, thrombo-embolic disease, and immune mediated glomerulonephritis. Taken together, the accumulated data suggest the possibility of accelerated autoimmunity-inflammation following vaccination.
Systemic manifestations of the alum-vaccine autoimmune-mediated macrophagic myofasciitis (MMF) include myalgias, arthralgia, marked asthenia, muscle weakness, chronic fatigue, fever and in some cases the appearance of a demyelinating disorder. Additionally, elevated creatine kinase (CK) and erythrocyte sedimentation rate as well as the appearance of autoantiboides, and myopathic EMG changes have also been documented. The local lesion of MMF was found to result from persistence of aluminium adjuvant at the site of inoculation months and even 8-10 years following immunisation. Muscle biopsy reveal infiltration of large PAS-positive, MHC-1-positive macrophages and CD8 T-cells, in the absence of muscle fibre damage. On electron microscopy, macrophages enclose cytoplasmic crystal material representing aluminium hydroxide. Another syndrome implicated to the adjuvant effect is the Gulf war syndrome (GWS). It is portrayed by chronic fatigue and other clinical manifestations that share many similarities with MMF. Multiple vaccinations performed over a short period of time were suggested to be the cause of this syndrome. Of note, during the Gulf war, the veterans’ vaccination protocol included the anthrax vaccine, vaccination administered in a six-shot regimen and adjuvanted by aluminium hydroxide and squalene. Previously both infectious agents and vaccines have been reported to precede the development of chronic fatigue syndrome (CFS) and fibromyalgia, and a role for Th-2 mediated immune response was suggested. Unlike the controversy regarding defined autoimmune diseases, a relationship between silicone implants and a collection of symptoms that do not fulfill any diagnostic criteria for a defined connective tissue disease was reported by several groups suggesting that indeed a non-defined syndrome may appear following exposure to silicone. Vasey et al. concluded that statistically significant increases in many signs and symptoms such as body ache, joints pain, myalgia, fatigue, impaired cognition and others, were associated with silicone breast implants.
The glycogen depletion associated with repeated bouts of prolonged exercise causes fatigue, and the associated decrease in blood glucose leads to a depletion of plasma amino acids, possibly predisposing to immuno-suppression and exercise-induced infection. The associated mobilisation of free fatty acids and a decreasing concentration of branch-chained amino acids (BCAA) increase tryptophan transport into the brain. Tryptophan is the precursor of serotonin, so that rising concentrations of tryptophan could cause fatigue and sleepiness, with a resulting depression of mood state. Some athletes have ingested tryptophan supplements in an attempt to induce growth hormone secretion, and there is suspicion of an association between this practice and onset of the eosinophilia myalgia. One double-blind, placebo-controlled trial found that the administration of high doses of essential fatty acids relieved chronic severe fatigue, myalgia, and various psychiatric symptoms. However, the mechanism of any benefit remained unclear, and the findings were not replicated when on repeating the study using the more precise Oxford Criteria for case definition (of CFS).
CFS patients also show increased resting concentrations of free tryptophan, but their concentrations are not increased further by exercise, perhaps because they do not usually engage in very heavy exercise. Some studies of athletes have reduced ratings of perceived exertion and delayed central fatigue by administering carbohydrates or BCAA. It is less clear why monosaccharide supplements should be needed in the general population. Nevertheless, a glyconutrient preparation providing the 8 monosaccharides needed to synthesize glycoproteins apparently reduces in vitro immunological changes in CFS. Patients with CFS sometimes benefit from taking B-group vitamin supplements an added salt.65 Magnesium concentrations influence the ratio of ATP to ADP, and could thus contribute to neurocirculatory asthenia and other symptoms of CFS, although as yet, there have been no trials of magnesium therapy in CFS. Low serum magnesium levels could arise from repeated heavy sweating, a restricted food intake, or an unbalanced diet with high carbohydrate and fibre content. A more direct suppression of immune function and resulting infection are common expressions of overtraining and stress in athletes. The functional characteristics of key leukocyte subsets are adversely affected by very heavy exercise, and since hypoxia suppresses T cell-mediated immune function, problems are particularly likely if athletes train at real or simulated altitude.69 Given the close interaction between the HPA axis and the immune system, there is also potential for a disturbance of immune function in CFS. Other suggestions of chronic inflammation include higher concentrations of C-reactive protein, constituents of class I MHC proteins, and the growth factors neopterin and TGF-j3.4 and benefit has sometimes been found from infusions of gammaglobulin, but IgE levels are unrelated to CFS.
Tasks that examine the relationships in function of these areas and other areas could include exposure to stressful memory-based tasks such as either letter- or number-based n-back tests (Goldberg et al., 2003; Harvey et al., 2005) a paradigm that would also test complaints of altered memory in CFS and PIF subjects, and confrontation with words that evoke illness responses during fMRI testing (Kircher et al., 2000). Newer mathematical approaches may allow evaluation of the temporal characteristics of connectivity (Rajapakse and Zhou, 2007), a reasonable approach while developments in measurement of function and imaging technology begin to catch up with needs in the field (Montoya et al., 2006; Westmeyer and Jasanoff, 2007).
Comparison of the origins of the words ‘‘ill,’’ ‘‘sick,’’ ‘‘illness,’’ ‘‘sickness,’’ and ‘‘disease’’ shows their interdependency (Oxford English Dictionary, 2007). Several authors, for example, Twaddle and Nordenfelt (1994) and Hofmann (2002) attribute disease to ‘‘an organic phenomenon (physiologic event) independent of subjective experience and social convention.’’ Whereas illness is considered a subjective undesirable state of health or a feeling state referred to by expression of symptoms. Although only ‘‘somatic’’ conditions are included in the Hofmann, Twaddle, and Nordenfelt discourses, psychiatric conditions such as depression would qualify for the illness label based on its definitional requirements, but as the biology of depression becomes clear, it will likely be considered a disease. The term ‘‘sickness behaviour’’ appears in two divergent contexts in the 20th century. It appears to have been introduced in evaluation of the sick role or illness behaviour associated with people who were considered to be sick in a sociological construct by Parsons (1958). The concept was expanded to include the term sickness behaviour by Twaddle (1979) who, as seen above, previously addressed the triad of disease, illness, and sickness. More recently, descriptions of the specific behaviour of diseased animals and humans as it relates to the consequences of infections and host responses to endogenously produced cytokines (Hart, 1988; Dantzer et al., 1998) also used the term sickness behaviour. In infectious diseases, sickness behaviour constitutes part of the disease process; it includes biological responses that are processed and perceived in turn as subjective symptoms. In modern immune concepts of disease, Twaddle’s concept of progression of disease to illness to sickness (Twaddle and Nordenfelt, 1994) could now be considered one of simultaneous events.
The cause(s) and the pathogenesis of CFS are as yet unknown but the central nervous system appears to be affected. Recent findings point at disturbances of the hypothalamic–pituitary–adrenal axis. The role of stress is not yet elucidated but psychosocial factors have been shown to have an influence on the onset and the severity of symptoms. CFS is often thought of as a modern illness. Taking a historical perspective, Wessely has argued that CFS is only ‘old wine in new bottles’, having been preceded by other diagnostic labels such as neurasthenia. The nature of CFS as a distinct disorder with well-demarcated boundaries has also been questioned. In fact, there are more commonalities than differences among many medically unexplained syndromes such as CFS, irritable bowel syndrome and fibromyalgia that they may all be considered to belong to a unitary group, functional somatic syndromes.
Greater numbers of minorities than expected have been found in community-based studies (Dinos et al., 2009). In a Chicago community-based study, the prevalence of CFS was higher for Latinos and African-Americans than for Caucasians (Jason, Richman et al., 1999). Symptom severity outcome measures revealed that when compared to Caucasians, minorities had more severe sore throat pain, fatigue following exercise, headaches, unrefreshing sleep, and poorer general health (Jason, Taylor, Kennedy, Jordan et al., 2000). In addition, Latinas who were older reported the highest relative severity of fatigue (Song, Jason, & Taylor, 1999). While CFS has frequently been referred to as the “Yuppie Disease” because it was thought to primarily affect middle to upper class women, it should be noted that these findings were obtained from tertiary care clinics (Friedberg & Jason, 1998). Bierl et al. (2004) reported on a national U.S. study that involved 2,728 households and found that lower income and education were associated with higher levels of chronic fatigue. Moreover, Jason, Jordan et al. (1999) found that individuals in a Chicago community- based sample with lower educational and occupational status reported higher levels of fatigue than those with higher educational and occupational status. Those from the lowest SES group had significantly higher disability ratings than those from the highest SES group. Psychological distress has been found to play a significant role in relation to the onset and/or course of many health conditions. Prospective studies have examined the relationship between chronic fatigue and psychological distress (Joyce et al., 1997). In one study, predictors of post-infectious fatigue six months following infectious illness included fatigue before infection and psychological distress before and at the time of infection (Wessely, Chalder, Hirsch, Wallace, & Wright, 1997). Bombardier and Buchwald (1995) also found the coexistence of dysthymia predicted poorer outcomes. In contrast, Hickie et al. (2006) followed up with people who had cases of mononucleosis (glandular fever), Q fever, and Ross River virus, who later met the criteria for CFS, and they found CFS was predicted largely by the severity of the acute illness rather than by psychological or demographic factors. Jason, Porter, Hunnell, Rademaker and Richman (2011) recently examined a group of individuals in a community-based sample with risk factor data collected from 1995-1997 (Wave 1) to their diagnostic status (CFS, Idiopathic chronic fatigue (ICF) which indicates the person has 6 months of fatigue but insufficient symptoms to meet the case definition of CFS, Medical reasons for the chronic fatigue, or controls) approximately 10 years (Wave 2). The CFS group at Wave 2 had significantly more impairment than the Controls only for Wave 1 Physical Composite Score, fatigue, and several somatic symptoms but not for any of the other measures of stress, support or coping. These findings suggest that physical measures of disability and fatigue, along with measures of specific somatic symptoms, better differentiate individuals who are later diagnosed with CFS than more psychosocial measures such as stress and coping. In addition, they found those in the group whose CFS had remitted over time were significantly younger than the group that developed CFS.
Background data collected from patients presenting with fatigue at the clinic of infectious diseases at Huddinge University Hospital, Stockholm was searched looking for differences to demographic and functional status for patients fulfilling criteria for chronic fatigue syndrome (CFS) and chronic fatigue (CF) using a cross-sectional questionnaire survey utilising a variety of instruments. Following thorough medical case investigation, no difference was found as to social situation, occupation and illness attributions for patients in the two categories. Patients with CFS reported in general a higher degree of ‘sickness’ with more self-reported somatic symptoms, more self-reported functional impairment and more absence from work. A higher degree of psychiatric comorbidity was observed in CF than in CFS patients. A majority of CFS patients (80%) had an acute infectious onset compared to 43% in the CF group. Presently used criteria might, then, define two different patient categories in a population characterized by severe, prolonged fatigue. Because CFS patients (compared to patients with CF) have more somatic symptoms, more often report an infectious, sudden onset and have less psychiatric comorbidity, and CF patients seem to have more of an emotional, burnout-like component one could speculate about the existence of different pathogenetic backgrounds behind the two diagnoses.
Classification of subjects
The controversy surrounding the possible causes of chronic fatigue syndrome (CFS) resurfaced this month, after results published in the Archives of Paediatrics and Adolescent Medicine showed that children with the disease had higher levels of oxidative stress and white blood cell apoptosis than controls—findings suggesting that the children with CFS are fighting a viral infection. The theory that CFS may be viral in origin first came to prominence in October 2009, when a study in Science showed that 68 (67%) of 101 patients with CFS who were tested were infected with the murine leukaemia virus XMRV, compared with eight (3·7%) of 218 controls. A string of negative results followed, with several groups unable to detect any trace of XMRV in patients with CFS. But a study published recently in Proceedings of the National Academy of Sciences reported a strong association between CFS and a murine virus very similar to XMRV. However, it is impossible to say at this stage whether these murine leukaemia viruses cause CFS, or whether they are bystander infections. It is already established that many cases of CFS are preceded by an acute viral infection. Studies in cohorts of patients with infectious mononucleosis caused by Epstein–Barr virus (EBV) show that a small proportion do not recover from post-infection fatigue, and subsequently go on to develop CFS. But it seems unlikely that CFS is a consequence of EBV, because most people make a full recovery. —The Lancet
Chronic fatigue syndrome (CFS) is characterized by prolonged and impairing fatigue of unknown aetiology. The standard definition of CFS requires severe fatigue of over six months duration that remains unexplained despite appropriate clinical medical evaluation along with four of eight signs and symptoms (e.g., post-exertional malaise and impaired memory or concentration). Immune dysfunction is a major etiological hypothesis, and could result from a chronic infection or an inappropriate response to an initial infection. The cause of chronic fatigue syndrome is unknown but infections with viruses have been suspected. Sullivan et al (2011) used a new approach to screen blood samples of 45 cases with chronic fatigue syndrome or idiopathic chronic fatigue for presence of known or novel viral infections using their unaffected monozygotic co-twins as controls. However, no novel DNA or RNA viral signatures were confidently identified. Four affected twins and no unaffected twins evidenced viremia with GB virus C (8.9% vs. 0%, p = 0.019), and one affected twin had previously undetected hepatitis C viremia. An excess of GB virus C viremia in cases with chronic fatigue requires confirmation; however, current impairing chronic fatigue was not robustly associated with viral infections in serum detectable by their method.
Persistent and unexplained fatigue has been observed as a sequela of acute infection since the first half of the 20th century and the period’s notable outbreaks of infectious disease (e.g., polio epidemics, influenza pandemics). From 1934 to 1984, there were several reports of infectious disease outbreaks simulating poliomyelitis though no causal pathogen was isolated from the majority of the cases. Clinical investigation of individuals who did not recover several years after initial infection showed persistent symptoms of fatigue, sleep disturbance and cognitive impairment. Following an outbreak investigation in 1984 by the Centers for Disease Control and Prevention (CDC) in Incline Village, Nevada, an international group of medical experts defined this protracted post-infection illness as chronic fatigue syndrome (CFS). Since then, post-infection illness that lasts for more than six months is a central component of CFS, and studies have shown that the incidence of CFS following infection with a number of different pathogens is about 10%.
A longitudinal cohort study to examine the effect of early clinical and demographic factors on occupational outcome, return to work or awarded permanent disability pension in young patients with chronic fatigue syndrome (CFS) from a written self-management programme, including a description of active coping strategies for daily life, resulted in about half of younger patients with CFS with long-term incapacity for work experiencing a marked improvement including full-time or part-time employment showing better outcomes than expected. Risk factors for transition to permanent disability were depression, arthralgia and disease duration.
The existence of post viral fatigue syndrome (PVFS. myalgic encephalomyelitis, Royal Free disease. chronic fatigue syndrome) has been doubted by many medical practitioners. Some of the scepticism may be due to the lack of a precise definition of this syndrome, and recent suggested definitions for PVFS will allow researchers to be confident that the same type of patient is being studied. In addition. there is a greater likelihood that causative agent(s) may be found and pathological mechanisms identified. The aetiology of PVFS is unknown. Two popular hypotheses are that the illness is a result of continuing viral infection or an abnormal immune response. Several abnormal immunological findings have been identified in PVFS patients, however results have shown discord. In addition, the causative agent may differ. with coxsackie virus infection being important in Britain but Epstein-Barr virus in American studies. Obviously, immunological abnormalities are expected more frequently in Epstein-Barr virus infections and therefore. in Britain where coxsackie virus infections appear more important , American findings of immunological abnormalities may not be relevant.
Estimates of the number of patients with CFS who can date their illness to a specific (presumably infectious) acute illness range from 20- 90%, with the highest percentages being recorded in adolescent populations. Accordingly our current results align closely with those of another study conducted specifically in a post-infectious patient population by Vollmer-Conna et al. (2007). The authors found no differences in the concentrations of IL-1b, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, and IFN-γ analyzed in serum. With the possible exception of elevated IL-2, we also did not find differences in the levels of these cytokines. Levels of IL-5, 8 and 23 were not measured in this earlier study.
Post-viral fatigue
The prospective primary care study of common viral infections from London showed that subjects in the viral infection group were not more likely to develop CFS than controls. But this does not answer the question as to whether specific infections such as EBV have a link with CFS. White et al. followed up 250 primary care patients presenting with glandular fever or upper respiratory tract infection (URTI). Forty-four percent had confirmed or probable EBV infections, 34% had non-EBV glandular fever and 22% had URTIs over a period of 6 months. The relative risk for the CDC-1994, the British and the authors’ empirical definitions were 5.1, 3.9 and 4.6, respectively. The prevalence was greatest for the British criteria on account of it being least restrictive. The authors also calculated the population attributable risk of 9% in cases of glandular fever. Cope et al. found that the following factors predicted CFS 6 months later in patients who were given a diagnosis of viral infection by their general practitioner: fatigue, a cognitive style of attributing symptoms to psychological causes and sick certification. These factors were different from the predictors of psychiatric ‘caseness’ which included past psychiatric history and psychological distress at the time of the viral illness. White et al. found a positive Monospot test and lower physical fitness to predict CFS 6 months following glandular fever. They replicated Cope et al.’s finding that premorbid psychiatric history predicted post-viral mood disorders, other predictors being social adversity and ‘emotional personality’. A recent study by Candy et al. adds to this literature by showing that expectations that the individual would take a long time to recover, or that the illness would have serious consequences were associated with a poor outcome at 6 months.
Some groups which have studied Gulf war veterans have looked for definitions of CFS in a Gulf war cohort. In a cross-sectional postal survey, Reid et al. studied the prevalence of CFS according to a modified CDC-1994 definition derived from their questionnaire. They estimated a prevalence of 2.1, 0.7 and 1.8% in cohorts who had been deployed in the Gulf, in Bosnia and had served during the Gulf war but had not been deployed there, respectively.
A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral micro-organisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome.
The neuroinflammation could have different triggers in different individuals. In some, it could be induced by brain infection (such as by chronic herpesvirus infection), autoantibodies, neurotoxins, or chronic stress. In others, inflammation outside the brain may be activating the innate immune system inside the brain, both through humoral signals that breach a porous blood-brain barrier and by retrograde signals sent up the vagus nerve. Several conference presentations included evidence that gut inflammation may be one peripheral trigger of neuroinflammation: the gut microbiota of patients with ME/CFS often include high numbers of proinflammatory species and low numbers of anti-inflammatory species.
With growing international interest in the illness, and increased research support from the NIH, the day is coming when physicians will be able to explain to patients not only that there is something wrong but also that advances in understanding the pathophysiology have led to effective therapy.
A number of prospective studies have therefore investigated the role of infections in the onset of CFS. Two of the earlier studies showed that common viral infections, such as upper respiratory tract infections, were not associated with the subsequent development of either chronic fatigue (CF) or CFS, and concluded that viruses did not play a role in the onset of the illness (Cope et al. 1994; Wessely et al. 1995). These periodic bursts of activity inevitably exacerbate symptoms and result in failure, which further reinforces the belief that they have a serious, ongoing illness. As time goes by, efforts to meet previous standards of achievement are abandoned and patients become increasingly preoccupied with their symptoms and illness. This results in chronic disability and the belief that one has an ongoing incurable illness which is eventually diagnosed as CFS. Potential participants were recruited through Diagnostic Medlab Auckland, the major provider of community clinical diagnostic services in Auckland (New Zealand), using consecutive sampling over a 20-month period. Individuals over the age of 16 years experiencing an acute case of GF were eligible to participate in the study. The findings from this study provide support for the cognitive behavioural model and a good basis for developing prevention and early intervention strategies for CFS.
A systematic review of psychosocial interventions in PIFS shows that while there are major gaps in the evidence, 9.22% of the sufferers have chronic fatigue syndrome six months following acute glandular fever. Physical deconditioning may play a key role in causing prolonged symptoms, and GPs should probably avoid advising rest for patients recovering from glandular fever. Research papers on the management of IM have often focused on the effect of drug therapies, particularly acyclovir (ACV) and steroids, on oropharyngeal symptoms or on rare complications, such as incipient airway obstruction. Generally, the literature on the management of the illness has been based on clinical experience, rather than formal research. The focus has often been on the acute phase, rather than prevention or management of any lingering symptoms. The literature tends to give guidance on symptomatic relief, on identifying and treating complications (such as severe pharyngeal oedema) on patients avoiding activity, particularly vigorous activity (because of the rare risk of splenic rupture), and on the need to rest.
- Fatigue is the most commonly noted symptom that can persist after the resolution of other acute symptoms in IM.
- Best evidence concludes that a fatigue syndrome exists in 9% to 22% of cases at six months after illness onset.
- The risk factor most consistently reported as predictive of chronic illness is reduced physical activity during the acute stage and in recovery from IM.
- Certain behavioural risk factors, such as reduced activity, may be amenable to interventions in primary care.
- The advice given by GPs to people with acute back pain has undergone a major shift in the last decade; perhaps a similar shift is needed for IM.
While viral serology is not necessary for diagnosis, CFS follows infection in at least a subset of cases. In adults, symptom onset coincided with apparent infection in up to 72 % of cases; in adolescents, infectious mononucleosis (IM) is the most commonly reported antecedent infection. The reported incidence of CFS following IM is 9-12%. Females appear more susceptible than males. Consistent with this, our group reported previously that 13, 7 and 4% of adolescents met criteria for CFS at 6, 12 and 24 months respectively post-IM, and at 6 months post-IM, 90% of the subjects with CFS were female, while at 12 and 24 months, 100% were female.
Infectious mononucleosis (IM) is an acute self-limiting disease caused by primary Epstein-Barr virus (EBV) infection. EBV persistently infects >90% of adults worldwide and is usually transmitted subclinically between young children via saliva; however, if primary infection is delayed until adolescence or early adult hood, IM develops in 25%-74% of cases. The classic presentation of IM comprises sore throat, fever, lymphadenopathy, and fatigue, with earlier studies, based on observation of hospitalized males, indicating complete recovery in 2-6 weeks. However, later surveys, based on general practice, have emphasized the frequent occurrence of prolonged fatigue. During IM, EBV infects B lymphocytes in the oropharynx, inducing their proliferation and dissemination. This invokes massive proliferation of virus specific, CD8+ cytotoxic T lymphocytes that colonize lymphoid tissues and invade other organs. It is thought that cytokines produced by these T cells, particularly interferon y and tumour necrosis factor cv, are responsible for the clinical picture of IM, and a cor relation between the level of T cell activation and the severity of symptoms has been noted. However, the pathogenesis of IM remains unclear. Sexual activity is a strong risk factor for both EBV seroconversion and IM in young adults, possibly by promoting trans mission of large amounts of virus, triggering the exaggerated T cell response. Genetic factors also play a part in IM development, because certain cytokine gene polymorphisms increase susceptibility to EBV infection, and we have recently identified 2 polymorphisms in the human leukocyte antigen class 1 gene that pre dispose to IM. Recruitment of case patients and control subjects. Participants were recruited during a study on EBV undertaken at Edinburgh University from 2000 through 2002, as described elsewhere. Briefly, students who were registering at the University Health Service (UHS) at the start of 4-year degree courses were invited to participate. EBV seronegative students were asked to return to the UHS if symptoms of IM developed, so that EBV serological tests could be performed. Students presenting to the UHS with clinical symptoms of IM who were not in the original study group could be included if they fulfilled the serological inclusion criteria. Diagnosis required either (1) a positive antiviral capsid antigen (VCA) immunoglobulin M (IgM) with demonstrable seroconversion to immunoglobulin G (IgG) anti VCA, or (2) a positive Monospot test with demonstrable seroconversion to IgG anti-VCA, or (3) a positive Monospot and anti-VCA IgM. Students with a negative Monospot and negative anti-VCA IgM tests were considered to have “IM-like” illnesses and formed a comparison group for flow cytometric analysis. Case patients with acute IM had significantly higher median numbers of total lymphocytes than did healthy control subjects (P<.001) or the IM-like group (P < .001). The case patients with acute IM had significantly higher numbers of CD3+, CD8+, CD56+, and yd T cells subsets (P<.001 for all), but not of CD19+ (P = .72) or CD4+ subsets (P = .86), compared with those of control subjects. Convalescent IM case patients had higher CD56+ and yd T cell counts than did control subjects or IM-like patients, and when convalescent samples were analyzed according to time since diagnosis, total lymphocyte counts and CD56+ natural killer (NK) cell counts remained significantly higher than those of control subjects for ^4 months, CD3+ and CD8+ T cells for < 15 days, and yd T cells for > 150 days.
While this trigger does not explain all presentations of CFS, it does represent a significant subset of patients, in particular in the paediatric population. Moreover though specific to the EBV pathogen, elements presented here may also be of relevance to other forms of CFS with an infectious aetiology. Constraints such as these further emphasize the importance of prospective studies and the need for much larger initiatives of this type in this and related patient populations.
In the multivariate prospective cohort analysis (Candy et al, 2003) no factors were found to predict poor outcome (fatigue) in 71 primary care patients with post infectious mononucleosis at all timepoints (3-monthly) to 1 year. Instead the pattern of predictors changed over time, partly but not completely consistent with our a priori predictions. Larger studies are needed to explore further the predictive nature of biopsychosocial factors in the pathogenesis of chronic fatigue related to IM. The psycho-behavioural predictors found in this study are amenable to intervention. Such interventions should be tested in randomized controlled trials. CFS is also associated with alterations in neuroendocrine function, with a relative under activity of the hypothalamic–pituitary–adrenal axis (HPA) (Cleare et al. 2001; Parker et al. 2001). While this seems a robust finding in individuals with established CFS, without prospective studies of individuals at high risk of developing CFS it is difficult to tell whether such changes play a causal role, or are a result of downstream factors such as sleep, deconditioning or circadian rhythm disruption (Spath Schwalde et al. 1992; Stupnicki & Obminski, 1992; Leese et al. 1996). Participants were also asked to supply saliva samples at 3 and 6 months. Postal questionnaires at 3 and 6 months repeated measures taken at baseline. Only the fatigue questionnaire was sent at 12 months.
Chronic fatigue syndrome (CFS) is a highly debilitating disorder characterized by persistent and unexplained fatigue resulting in severe impairment in daily functioning (Fukuda et al. 1994). There has been much debate and controversy about the aetiology of the disorder. One school of thought argues that CFS is caused or precipitated by acute infection, as many patients predate their illness onset to an initial infection from which they never recovered (Wessely et al. 1991). Two of the early prospective investigating the role of infections in the onset of CFS showed that common viral infections—such as upper respiratory tract infections—were not associated with the subsequent development of either chronic fatigue or chronic fatigue syndrome, and concluded that viruses did not play a role in the onset of the illness (Cope et al. 1994; Wessely et al. 1995). Subsequent studies, however, have shown that certain more severe infections play a role in the onset of chronic fatigue syndrome, including that of infectious mononucleosis or glandular fever (White et al. 2001; Moss-Morris & Spence, 2006), hepatitis (Berelowitz et al. 1995), viral meningitis (Hotopf et al. 1996), Q fever (Wildman et al. 2002) and Ross River virus (Hickie et al. 2006). Using the cognitive behavioural model to guide our choice of predictor variables, the purpose of this study was to investigate the role of psychological variables, alongside a clearly identifiable physiological variable, GF, in the precipitation of and early perpetuation of CFS. There is good evidence that glandular fever is a risk factor for the development of CFS (White et al. 1995; Buchwald et al. 2000; Candy et al. 2002). The cognitive behavioural model of CFS suggests the illness is caused through reciprocal interactions between physiology, cognition, emotion and behaviour, suggestions supported by findings from prospective cohort studies. These studies show a slight trend, at three months, for chronic fatigue cases to report fewer symptoms, suggesting that severity of the acute illness was not a risk factor in the onset of CFS. Consistent with prior findings for an association between fatigue and female gender, cases of CFS at 6 months after infection were significantly more likely to be female (Buchwald et al. 2000; Candy et al. 2003). The 8% prevalence rate of CFS at 6 months in this study is comparable with the only other study using the Fukuda criteria, that found a CFS rate of 9% at six months after infection (White et al. 1998).
A hypothetical paradigm for evaluating chronic Q fever sequelae, derived by analogy from mycobacterial host-parasite relationships—that is, one where long-term, low-level bacterial persistence is also a feature—is one of anergic or hypersensitive polar disease states with some intermediate “reactive” stages. At the anergic pole of this spectrum lies subacute Q-fever endocarditis, with low indices of cell-mediated immunity (CMI), such as lymphocyte mitogenic responses to Q-fever antigens. Scanty inflammatory infiltrates but large numbers of coxiellas are seen in valve vegetations, generally also with very high levels of serum antibody. Coxiellas in valves are readily detected by animal inoculation, cell culture, or PCR gene amplification. A French study of cytokine response or release patterns from monocytes or PBMC in endocarditis patients has shown upregulated IL-10 and TNFa production, downregulated IFNγ responses, with increased TNF-R 75 production.
Therapeutic use of IFNs α, β, and γ, induce fever, chills, and symptoms of sickness-behaviour, including malaise and anorexia, that appear within 24 hours following injection and subsequently diminish over the following weeks.
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Editorial. www.thelancet.com Vol 376 September 18, 2010: S930.
End Notes:
[1] Demitrack et al. (1991).
[2] Hamilos et al. (1998). Cleare (2004). Jerjes et al., (2006).
[3] Bou-Holaigah et al. (1995). Stewart (2000).
[4] Afari and Buchwald (2003).
[5] White et al. (1998).
[6] Medshitov and Janeway (2000). Janeway and Medshitov (2002). Tosi, (2005).
[7] http://www.georgnorthoff.com/s/Am-I-my-Brain_Personal-Identity-and-Brain-Identity_low.pdf.
[8] Tracey (2002). Maier (2003). Watkins et al. (2007). Farina et al. (2007).
