Chronic Fatigue Syndrome

Amit Sapra; Priyanka Bhandari

Chronic Fatigue Syndrome

Earn CME/CE in your profession:

Free Review Questions

Continuing Education Activity

Chronic fatigue syndrome, also known as myalgic encephalomyelitis, is a complex multisystem disease commonly characterized by severe fatigue, cognitive dysfunction, sleep problems, autonomic dysfunction, and post-exertional malaise, which can severely impair patients' ability to conduct the activities of daily living. Therefore, early diagnosis and prompt treatment are critical to prevent high morbidity and its overwhelming effect on the quality of life. This activity reviews the evaluation and treatment of chronic fatigue syndrome and highlights the interprofessional team's role in evaluating and treating patients with this condition.

Objectives:

Identify the etiology of chronic fatigue syndrome.
Review the appropriate evaluation of chronic fatigue syndrome.
Outline the management options available for chronic fatigue syndrome.
Describe interprofessional team strategies for improving care coordination and communication to ensure the best outcomes for patients with chronic fatigue syndrome.

Introduction

Chronic fatigue syndrome (CFS) is a chronic disease that potentially affects about two million Americans.[1] The United States Public Health Services initially described it during an epidemiological study of Los Angeles County during the summer of 1934. Chronic fatigue syndrome, also called myalgic encephalomyelitis, is a complex multisystem disease commonly characterized by severe fatigue, cognitive dysfunction, sleep problems, autonomic dysfunction, and post-exertional malaise, severely impairing activities of daily living. Outcomes become worse due to the condition remaining undiagnosed for years, secondary to inadequate medical teaching on the subject, provider bias, and confusion regarding the diagnosis and treatment of the disease.[1]

CFS does not only present with fatigue but also cognitive dysfunction and impairment of routine functioning that persists for six months or more. CFS is a biological condition, not a psychological disorder. The exact pathogenesis remains to be fully understood. Various mechanisms and biochemical changes have been implicated that affect immune function, hormonal regulation, and response to oxidative stress. It also includes natural killer cell dysfunction and/or T-cell dysfunction, elevated cytokines, and autoantibodies.[2] The infectious cause has been proposed, but no causal relationship has been identified.[3]

Patients with CFS can sometimes present to the emergency department with a list of complex symptoms, such as orthostatic intolerance, postexertional malaise (PEM), fatigue, and diarrhea.[4]

Etiology

The etiology of chronic fatigue syndrome (CFS) is controversial, complicated, and incompletely understood. Controversy exists about single versus multiple causations. Many theories exist regarding the involvement of infections, the immune system, and genetics in this complex interplay.

Genetics

Increasing evidence supports the role of genetic susceptibility in patients with CFS. Many studies have reported the role of family history in the development of CFS or similar fatigue-like symptoms.[5] Studies from the twin registry also have shown increased familial and genetic predisposition to the condition.[6][7] A study observed variability in the expression of specific genes in patients with CFS, particularly after exercise, which affects the metabolism and immune responses.[8] In another study, an association was reported between CFS and specific genetic mutations and viral infections.[9]

Infection

Various infectious etiologies, including the Epstein-Barr virus (EBV), the human herpesvirus (HHV)-6, and the human parvovirus B19, are hypothesized to trigger the disease.[10][11][12][13]

Speculations are that in a few patients, the acquisition of viral infections like infectious mononucleosis triggers the onset of the disease process.[14][15][16]

Researchers have detected anti-HHV-6 IgM antibodies and HHV-6 antigens more commonly in the peripheral blood of patients with chronic fatigue syndrome than in the general population, indicating higher prevalence and higher reactivation of the virus in this cohort.[17][18][19][20]

Parvovirus B19, both with and without viremia, has been implicated in developing and triggering chronic fatigue syndrome.[21] These patients have higher levels of tumor necrosis factor and interferon-gamma.[22]

Alterations in the Immune System

It has been observed that alterations in the levels of CD 21+ CD19+ and activated CD5+ cells in patients with chronic fatigue syndrome.[23]

There is also a reported decrease in transitional B cells and plasmablasts and an increase in the population of CD24+ B cells in these patients.[24][25] Researchers have also found elevations in the levels of immunoglobulins IgG in several studies, again pointing to alteration in the immune functioning of these patients.[26][27] Several studies have also described the presence of autoantibodies against nuclear and membrane structures as well as against neurotransmitter receptors.[28][29][30][31]

Epidemiology

Studies have given different prevalence rates for chronic fatigue syndrome based on the type of definition used, the type of population surveyed, and the study design used.[32] Studies have given a current prevalence rate ranging from 0.007% to 2.8% in the general adult U.S. population and from 0.006% to 3.0% in the primary care population.[33][34][35][36][37] Studies conducted from 1993 through 1999 reported a prevalence of 0.004% to 0.56%, whereas more recent studies have reported prevalence rates of 0.24% to 2.6%.[38] As per the study conducted by Bierl and colleagues in 2004, about 2.2 million American adults suffer from CFS-like illness.[39] They estimated that about 1,197 people per 100,000 suffer from CSF and CFS-like illnesses.[39]

Studies have found that the prevalence is significantly higher between 40 and 70 years of age.[40] Women suffer from it more often than men.[41] The prevalence seems higher in the White population than in the non-White population.[41] Studies have also reported a markedly higher prevalence in the low-income cohort than in the higher-income and higher-educated cohort, suggesting the role of social risk factors such as stress in the causation of CFS.[41][39][40] No regional differences were noticed in the country as far as CFS prevalence is concerned.[39]

Pathophysiology

Alterations in the Immune System

The pathophysiological mechanisms leading to chronic fatigue syndrome are not entirely understood.[42] It is proposed that an alteration in the nervous system occurs secondary to the body’s unintended responses to commonly encountered antigens, leading to changes in the cell-mediated immunity, activation of oxidative pathways, and alteration in the neuroendocrinal and autoimmune responses against neurons.[43] Multiple studies have shown alterations in the functioning of the natural killer (NK) cells, interleukins profile, and the decreased response of T cells to specific antigens.[42]

There is evidence of ongoing inflammation, as indicated by increased production of various proinflammatory interleukins, which also explains malaise and flu-like symptoms about which the patients often complain.[42]

Increased Oxidative Stress

Some studies report chronic fatigue syndrome patients to have significantly increased oxidative stress, which plays a vital role in the etiopathogenesis of the disease. There is an increase in oxidative stress biomarkers like oxidized LDL and certain prostaglandins and, at the same time, a decrease in the amounts of antioxidants like glutathione.[44][45] The oxidative damage transforms the fatty acids and proteins into immunogenic targets.[46] The free radicals also damage the electron transport chain (causing impaired energy production) and mitochondria.[47] The mechanism underlying mitochondrial dysregulation is not entirely known.[48][49][50]

Oligoadenylate Synthetase/RNase L Pathway

The association between the onset of CFS with a viral infection has always been speculated. One of the interferon-activated antiviral pathways involves activating the 2’-5’-oligoadenylate (2-5A) synthetase/RNase L system.[51] Severe deregulation of this antiviral pathway occurs in CFS, which leads to a decrease in the apoptotic activity in the cells.

Alteration of Natural Killer (NK) Cells

Studies have shown a lower number of CD3-CD57 white cell lymphocytes, which are a type of NK cell, whereas the levels of the cytotoxic T cells were not changed.[52][53][54]

B Cell Impairment

The profile of B cell subpopulations may differ in CFS compared with controls. CFS is associated with increased production of the CD20+ CD5+ B cell phenotypes correlating with increased autoantibody production and overexpression of CD21 markers acting as receptors for some viruses.[24][25]

Immunoglobulins

There is also an alteration in the immunoglobulin number and distribution in patients with chronic fatigue syndrome. The total immunoglobulin G (IgG) level, particularly subclasses IgG1 and IgG3, is substantially lower. In contrast, there is an increase in IgA and IgM serum levels against the lipopolysaccharides of normal gram-negative bacteria due to alterations in gut permeability.[55][56] These can also serve as corroborative evidence for the provider about the patient suffering from CFS.

Autoimmunity

Studies have also detected autoantibodies against certain neurotransmitters and neurons, leading to alterations in neurotransmitter response, sleep patterns, and neurocognition.[30][57] Researchers have found antinuclear antibodies (ANA), anti-dsDNA antibodies, and antibodies against neuronal and endothelial cells in these patients.[58] Moreover, antibodies against the muscarinic M1 acetylcholine beta-adrenergic receptors have been detected in these patients.[30][13] Disturbance in these receptors could explain symptoms of autonomic dysregulation in these patients.[59]

Alterations in the Central Nervous System

Neuroinflammation and Role of Glial Cells

The presence of proinflammatory changes causes speculation about the involvement of neuroinflammation in the pathogenesis and clinical presentation of the disease process.[60] Multiple studies show that the constant proinflammatory state that occurs in CFS causes activation of glial cells, specifically microglia and astrocytes. These activated glial cells produce the expression of a translator protein, which appears to activate inflammation in the central nervous system.[61] The increase in glial activation leads to an increase in neuronal excitation and neuronal inflammation, which is supposed to be the leading cause of chronic pain symptoms in these patients.[62] Studies are also evaluating the role of “glial toxins” produced by multiple viruses and bacteria, leading to direct damage to these glial cells.[63]

Neuronal Sensitization

The hypothesis about neuronal sensitization proposes an exaggerated response to painful stimuli in patients with CFS due to the chemical and structural changes at the central nervous system level.[62] This exaggerated response leads to the formation of sensitized neurons that keep the stimulus going due to the process of “kindling.”

Alterations in the Neuroendocrine System

Changes in Serotonin Transmission

Central fatigue, a key symptom in patients with chronic fatigue syndrome, is hypothesized to be due to excess levels of serotonin and its metabolites in the central nervous system of these patients.[64] The excess serotonin leads to inhibition of the action potential generation and thus reduces motor activity and appears to be a leading contributor to the fatigue symptoms of these patients.[65][66]

Hypocortisolism

It is also theorized that there are low circulating cortisol levels in patients with chronic fatigue syndrome secondary to dysfunction in the hypothalamic-pituitary axis (HPA). Cortisol is the principal hormone of the HPA and leads to the cortisol awakening response (CAR). This response is deficient in patients with CFS, leading to post-exertional malaise.[67]

Genetic Predisposition

Studies have shown an interaction between changes in the genes secondary to changes in the environment, leading to epigenetic modification. DNA methylation appears to be the most studied of these epigenetic modifications that can alter the expression of the gene concerning the environmental stimuli and lead to the development of the disease process.[68]

History and Physical

The hallmark symptom of chronic fatigue syndrome is the post-exertional fatigue associated with numerous neurological, cardiovascular, respiratory, and gastrointestinal complaints.[68] The fatigue described by patients is worsened by exertion and low upright posture, not relieved by rest, and no medical reason can be found.[69] Patients often state that they have had high fitness levels before the onset of fatigue.[70] Patients describe the beginning of the fatigue rather abruptly, typically associated with a flu-like illness.[71] They also describe post-exertional malaise, where regular activity is followed by symptoms of worsening discomfort and fatigue, with delayed recovery, usually taking more than one day.[72] Patients also complain of new-onset chronic headaches with varied weekly fluctuations.[72] Muscle pain is seen more commonly in pediatric patients and also could be a feature of comorbid fibromyalgia.[73]

Patients can also report joint pains, and there could be an associated autoimmune rheumatological condition.[73] There are often reports of disturbed sleep and not feeling fresh the next morning, leading to daytime hypersomnolence and nighttime insomnia.[72] Also, there are complaints of cognitive decline with slowed mental processing speed, poor learning abilities, impaired processing of new information, memory decline, decreased attention span, and poor multitasking ability.[74] Besides, these patients can also have autonomic manifestations, including nausea, vomiting, drenching night sweats, dizziness, and intolerance to alcohol and other medications.[75][76] Patients can also exhibit symptoms of uncontrolled anxiety, panic attacks, and impaired social functioning.[77][78] Most of these patients have a decreased ability to work.[79]

Evaluation

Chronic fatigue syndrome (CFS) is a diagnosis made on clinical examination after excluding other possible etiologies.

Initially, when the etiological considerations were considered mainly viral in origin, the Center for Disease Control and Prevention (CDC) U.S.A., in 1988, came up with the criterion for the same with the primary focus on the physical symptoms. The Oxford criterion was developed in 1991 and defined a case of chronic fatigue syndrome where mild to severe symptoms of fatigue, myalgias, and tiredness were present.[77] The Oxford criterion states fatigue to be the primary symptom which should have a definite beginning and should be severe, disabling, and affecting mental and physical functions. These symptoms should have been present for a minimum of six months and should be affecting the patient more than fifty percent of the time. There was a need for other symptoms like myalgias, mood, and sleep disturbances to be present as well. Exclusion criteria included those known to have a medical condition that caused fatigue and those diagnosed with mental health disorders like schizophrenia, mania, depression, eating disorders, substance abuse, or known organic brain pathology.[77]

Subsequent conclusions stated that the Oxford criterion was over-inclusive and had a low threshold that recruited patients with milder symptoms, leading to the generalization of treatments for all patients. Hence, the treatment guidelines could not be generalized to patients with severe symptoms, chronic pain, post-exertional malaise, and other conditions that mimicked chronic fatigue syndrome.[80][81][82]

Considering the need for revision of the diagnostic criterion, the CDC, in the year 1994, came up with a broader definition for chronic fatigue syndrome developed by Fakuda and colleagues.[83] As per these criteria, the patient should have severe fatigue for more than six months as well as at least four of the following symptoms: a new type of headache or a change in the pattern or severity of the headache, myalgias, pain in multiple joints, post-exertional malaise lasting more than one day, sore throat, tender lymph nodes, unrefreshing sleep and significant impairment in short term memory or concentration.

The modified CDC criterion was extensively used until 2015 when the Institute of Medicine (IOM) proposed the criterion to diagnose chronic fatigue syndrome.[84] The current IOM criterion was developed after reviewing the 1994 CDC guidelines by Fakuda and colleagues, the 2003 Canadian clinical case definition for CFS, the 2007 clinical guidelines for CFS from the British National Institute for Health and Clinical Excellence (NICE) along with the 2010 revised Canadian consensus criteria for CFS (Revised CCC).[84]

2015 IOM Diagnostic Criteria for CFS

Diagnosis of chronic fatigue syndrome requires the presence of the following three symptoms for more than six months as well as the intensity of the symptoms should be moderate or severe for at least 50% of the time.

The three main symptoms include:

Fatigue - A noticeable decrease or impairment in a patient's ability to engage in activities they would have enjoyed before the onset of the illness. This impairment continues for more than six months and is associated with new-onset severe fatigue unrelated to exertion and not relieved by rest.
Post-exertional malaise - Patients experience worsening symptoms and function after exposure to physical or cognitive stressors, which they previously well tolerated.
Unrefreshing sleep - patients feel tired after a night's sleep.

Criterion fulfillment for diagnosis requires the three above-stated symptoms plus one of the additional below-mentioned symptoms.

Cognitive impairment - Problems with the thought or executive function worsened by exertion, effort, stress, or time pressure.
Orthostatic intolerance - Worsening of symptoms upon assuming and maintaining an upright posture. Although not necessarily abolished, symptoms are improved by lying back down or elevating the feet.[84]

The typical approach to a patient with chronic fatigue should begin with a history and physical examination, identifying the underlying symptoms and ruling out any serious illnesses. The providers should use a validated clinical questionnaire like the DePaul symptom questionnaire or the Center for Disease Control Symptom Inventory.[85][86]

There are no pathognomonic or diagnostic tests or single biomarkers of CFS. Tests to rule out other etiologies are undertaken in the context of the particular patient. The standard laboratory tests include urinalysis, complete blood count with differential, blood chemistries, thyroid function tests, muscle enzymes like creatine kinases, and C- reactive protein.[83] The national institute for clinical excellence (NICE) also conducts tests for gluten sensitivity and recommends using immunoglobulin A endomysial antibodies, urine drug screening, and rheumatological antibodies as indicated. It also recommends against using viral titers unless necessary after the patient's clinical examination.[87]

Treatment / Management

Non-Pharmacologic Management

There is some debate about the appropriate treatment of chronic fatigue syndrome. A randomized control trial conducted in 2011 in the United Kingdom compared the effectiveness and safety of cognitive-behavioral therapy (CBT), graded exercise therapy (GET), adaptive pacing therapy (APT), and specialist medical care in the management of chronic fatigue syndrome. Overcoming fatigue and improvement of physical function were taken as measures of effectiveness, while safety assessment comprised recording all adverse effects. The results showed that CBT and GET improved outcomes when used together, whereas APT was not a helpful addition.[80]

Further analysis of the available data questions the statistical significance of the benefits of CBT and GET.[88] The CDC recommends treating associated depression, stress, and anxiety but states that this is not a cure for CFS. Techniques like deep breathing and muscle relaxation, massage, yoga, and tai chi may be of benefit.

Treatment for any comorbid condition should be undertaken to minimize symptom burden.[83][89]

During the CBT sessions, the therapist emphasizes the role of the thought process and its impact on the patient's actions and feelings and recognizes behaviors that cause them to feel more tired and minimize them. Multiple trials and Cochrane reviews have shown the positive benefits of CBT in improving fatigue, mood, and post-exertional malaise in both adolescent and adult patients.[89][90][91][92] Studies have also shown lower school absences when CBT is provided to the adolescent population.[93]

GET involves a supervised, gradual increase in the duration and intensity of physical activity. After the PACE trial, this therapy got much publicity, which showed effectiveness for fatigue and functional impairment with the GET.[80] The trial encouraged the participants to gradually increase the timing of their physical activity to a final goal of 30 minutes, spread over 52 weeks to a final goal of 30 minutes of light exercise five days per week while trying to avoid overexertion. Other studies have also supported its efficacy.[94][95][96] However, CBT and GET can be adjunct management options, but they are not curative.

Activity management is also called pacing. The goal is to learn to balance rest and activity to avoid flare-ups. These can be caused by exertion that patients cannot tolerate.

Pharmacologic Management

Pain Medications

Nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, are used due to their action in relieving pain and associated inflammation.[97][98] Opioid medications are addictive and hence only used for very severe cases for the shortest possible duration.[99]

Tricyclic Antidepressants

Multiple tricyclic antidepressants have shown varying degrees of success in improving sleep, pain levels, and fatigue severity.[97] The doses used here are typically lower than the doses used in the treatment of depression.[100]

Selective Serotonin Reuptake Inhibitors (SSRI) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)

Many SSRIs like fluoxetine, sertraline, and paroxetine have been used to treat depression and anxiety, which either accompany the disease process of chronic fatigue syndrome or occur as a consequence. SNRIs have the added benefit of providing neuropathic pain relief besides the antidepressant effect. However, neither SSRIs nor SSNRIs directly affect the underlying pathophysiology of the disease process.[80]

Antiviral Therapy

Several antiviral medications have been tried in these patients, but most of these studies have been inconclusive.[101][102] Randomized controlled trials (RCTs) comparing the effect of nucleotide analog inhibitors like acyclovir, valacyclovir, and ganciclovir versus placebo have shown no difference in symptom control.[103] Studies using interferons versus placebo in chronic fatigue syndrome also did not show evidence of clear benefit.[104]

Immunoglobulin

A systemic review conducted by Whiting et al. in 2001 evaluated five randomized controlled trials on the use of immunoglobulins in patients with chronic fatigue syndrome. It revealed positive results in four of them.[80] Unfortunately, other studies did not report any benefit and, in fact, concluded the potential dangers of immunoglobulins.

Corticosteroids

Multiple RCTs and systemic reviews performed with steroids in 2005 showed varying responses. One systemic review conducted in 2015 showed a weak benefit from low-dose hydrocortisone, but the effect was only short-lived and was associated with adverse effects.[105]

Complementary and Alternative Medicines

Systemic reviews of the studies using essential fatty acids, magnesium, acetyl-l-carnitine, vitamin B12, and antioxidants have shown only partial response and require further studies to establish a definitive relation.[106]

Newer Treatments and Trials

Rintatolimod

Rintatolimod is a newly approved immunomodulator and an antiviral drug for treating chronic fatigue syndrome in Canada and Europe.[107] An RCT published in the Journal of the American Medical Association (JAMA) in 2001 showed the medication to be of some benefit to these patients.[108] The U.S. FDA rejected the drug to be marketed in the U.S. for CFS treatment, citing insufficient safety and efficacy data.

Rituximab

Rituximab is an anti-CD20 monoclonal antibody causing the depletion of B cells. An initial small double-blind, placebo-controlled trial of 30 patients with CFS receiving rituximab showed some benefit, leading the researchers to hypothesize that B cells might have a significant role in the pathogenesis of some patients with chronic fatigue syndrome.[109] However, a more extensive study showed no fatigue difference between patients who received rituximab versus those who did not. Also, patients receiving rituximab showed more adverse effects, including neutropenia and infections.[110]

Fecal Microbiota Transplantation

Alteration in gastrointestinal (GI) microbiota in CFS patients has been hypothesized as one of the etiologies.[111][112] Trials of fecal microbiota transplantation are an exciting, relatively safe, and rapidly growing treatment modality that is currently undergoing experimentation to manage multiple medical conditions, including CFS.[113][114] The process involves the transfer of feces from a healthy donor into a patient's gut.[115] In recent years, numerous studies have shown significant symptom relief in these patients after the fecal microbiota transfer provides promising therapeutic insights.[116][117]

Even though there has been some success with the fecal microbiota, it is still too early to conclude anything. However, it opens doors for future research in this direction.

Differential Diagnosis

Chronic fatigue syndrome can potentially affect the instrumental activities of daily living (IADLs), such as cleaning, laundry, driving, and managing finances.[118] Hence, the providers must be able to diagnose this condition but, at the same time, also be able to differentiate it from other commonly encountered disorders in clinical practice, which can have overlapping presentations.

Chronic Fatigue

Even though chronic fatigue syndrome has fatigue as one of the three mandatory symptoms, it is a complex multisystem neurological disease with evidence of inflammation in the brain, hence the term myalgic encephalomyelitis.[119] On the other hand, chronic fatigue lacks the associated post-exertional malaise, unrefreshing sleep, and cognitive impairment.[119] To minimize the confusion with the terminology, the Institute of Medicine (IOM) has even suggested switching the terminology from chronic fatigue syndrome to "systemic exertion intolerance disease (SEID)" instead of CFS.[1]

Rheumatological Disorders

Fibromyalgia, polymyalgia rheumatica, polymyositis, and autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren syndrome present a significant diagnostic dilemma for the provider.[120][121][122] It requires proper history, clinical examination, and laboratory testing for autoantibodies before arriving at the correct diagnosis.

Psychiatric Disorders

Roughly 20% of the patients presenting to primary care clinics have an underlying undiagnosed depressive illness and a targeted mental health history is critical.[123] There could be a range of undiagnosed or underdiagnosed disorders like major depressive disorder, bipolar disorder, eating disorder, schizophrenia, somatoform disorders, and substance abuse. It is of the utmost importance to remember that in the elderly, symptoms of fatigue, unrefreshing sleep, and cognitive decline can be very much part of the symptom complex of late-onset depression.[124]

Endocrine Disorders

There could be adrenal abnormalities (Addison disease, adrenal insufficiency, Cushing disease), thyroid abnormalities (both hypothyroidism and hyperthyroidism), and diabetes mellitus, which can mimic symptoms of chronic fatigue syndrome.

Hematological and Oncologic Disorders

Undiagnosed malignancies can present with symptoms of fatigue and warrant a search for underlying cancer with age-appropriate screening. However, age alone should not be the only determining criterion for ordering these screenings.[125] Anemia from any cause can present with excessive tiredness and fatigue.[126][127][128][129]

Infectious Diseases

Infectious diseases like the human immunodeficiency virus, tuberculosis, and chronic hepatitis can have ongoing fatigue as their initial presentation.

Gastrointestinal Disorders

Inflammatory bowel disease can present with chronic fatigue symptoms.[130] Celiac disease can present with fatigue and sometimes even without gastrointestinal symptoms.

Neurological Disorders

Fatigue is the main presenting feature of multiple sclerosis.[131] Dementia, which has cognitive impairment as its major presentation, can cause a diagnostic dilemma, as can pseudodementia.

Age-related Orthostatic Hypotension

It is again imperative to recognize that there are age-related changes in blood vessels, causing decreased autonomic responsiveness, which worsens with inadequate fluid intake and polypharmacy.[132]

Respiratory Disorders

Chronic respiratory conditions like chronic obstructive pulmonary disease (COPD) and sarcoidosis can present with chronic fatigue.[133]

Sleep Apnea

Undiagnosed obstructive sleep apnea can present with fatigue and unrefreshing sleep, two of the main diagnostic criteria for chronic fatigue syndrome. This is diagnosed by polysomnography.[134]

Prognosis

Chronic fatigue syndrome has no cure, and the symptoms can persist for years. Its clinical course fluctuates between remissions and relapses. According to one prospective study, around 50% of patients with CFS may return to part-time or full-time work.[135] Factors associated with poor prognosis include longer duration of illness, comorbid depression, severe fatigue, and anxiety.[136]

Favorable outcomes are associated with less severity of fatigue at baseline, a better sense of control over symptoms, and the absence of any attribution of the disease to a physical cause.[137] Although a considerable burden of morbidity is linked with CFS, there is no remarkable evidence of increased mortality.

Complications

As with any chronic illness, it is very common for people with chronic fatigue syndrome to experience depression, stress, and anxiety. While chronic fatigue syndrome is not a psychological condition, it is debilitating. Good days or bad days can be unpredictable. Patients experience ongoing challenges in their education, career, and personal life as they work to balance how they feel about their obligations and desires. Many people with CFS describe feeling demoralized or even, at times, hopeless.

Deterrence and Patient Education

Living with chronic fatigue syndrome can be stressful, as the symptoms can affect the quality of life. Most people are generally healthy and active before developing CFS, making it particularly distressing. The most crucial factor for patients to successfully cope with CFS is establishing a strong relationship with an experienced healthcare provider. Having a provider that patients can trust, who listens to them and understands that their symptoms are real, can be validating and helpful. While it is discouraging to know that there is no quick cure for CFS, an experienced provider can work with the patient to find ways to manage their symptoms and maximize their quality of life.

Enhancing Healthcare Team Outcomes

Chronic fatigue syndrome frequently poses a diagnostic dilemma. The hallmark symptom is post-exertional fatigue associated with numerous neurological, cardiovascular, respiratory, and gastrointestinal complaints. Patients can also exhibit uncontrolled anxiety, panic attacks, and impaired social functioning. Chronic fatigue syndrome is a diagnosis made on clinical examination after excluding other possible etiologies. Therefore, it is essential to consult with an interprofessional team of specialists, including a pain specialist, psychiatrist, psychotherapist, nursing staff, other clinicians (MDs, DOs, NPs, or PAs), and possibly a physical therapist and/or pharmacist, depending on the treatment course taken. Even though chronic fatigue syndrome has fatigue as one of the three mandatory symptoms, it is a complex multisystem neurological disease with evidence of inflammation in the brain. As the term myalgic encephalomyelitis indicates, a neurology consultation can be useful when indicated.

All interprofessional team members must follow the patient, record and progress or deterioration of their condition, and inform other team members so changes in the management approach can occur if necessary. Open communication and diligent documentation are essential to the interprofessional strategy so that all team members can access the same patient data. This will help drive better outcomes. [Level 5]

The primary non-pharmacological treatment modalities are cognitive behavior therapy and graded exercise therapy. There is a wide range of medications that can be used for CFS. They range from NSAIDs to antidepressants; therefore, a pharmacy consult is in order. The pharmacist can perform medication reconciliation and check medication dosing, reporting any concerns to the other team members as appropriate.

A broad range of differential diagnoses should be considered before diagnosing chronic fatigue syndrome. However, consultation with an interprofessional healthcare team is recommended to improve outcomes.

Details

References

[1]

. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Military medicine. 2015 Jul:180(7):721-3. doi: 10.7205/MILMED-D-15-00085. Epub [PubMed PMID: 26126237]

[2]

Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, Chu L, Younger JW, Tato CM, Davis MM. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proceedings of the National Academy of Sciences of the United States of America. 2017 Aug 22:114(34):E7150-E7158. doi: 10.1073/pnas.1710519114. Epub 2017 Jul 31 [PubMed PMID: 28760971]

[3]

Cortes Rivera M, Mastronardi C, Silva-Aldana CT, Arcos-Burgos M, Lidbury BA. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review. Diagnostics (Basel, Switzerland). 2019 Aug 7:9(3):. doi: 10.3390/diagnostics9030091. Epub 2019 Aug 7 [PubMed PMID: 31394725]

[4]

Timbol CR, Baraniuk JN. Chronic fatigue syndrome in the emergency department. Open access emergency medicine : OAEM. 2019:11():15-28. doi: 10.2147/OAEM.S176843. Epub 2019 Jan 11 [PubMed PMID: 30666170]

[5]

Hickie I, Bennett B, Lloyd A, Heath A, Martin N. Complex genetic and environmental relationships between psychological distress, fatigue and immune functioning: a twin study. Psychological medicine. 1999 Mar:29(2):269-77 [PubMed PMID: 10218918]

[6]

Hickie I, Kirk K, Martin N. Unique genetic and environmental determinants of prolonged fatigue: a twin study. Psychological medicine. 1999 Mar:29(2):259-68 [PubMed PMID: 10218917]

[7]

Buchwald D, Herrell R, Ashton S, Belcourt M, Schmaling K, Sullivan P, Neale M, Goldberg J. A twin study of chronic fatigue. Psychosomatic medicine. 2001 Nov-Dec:63(6):936-43 [PubMed PMID: 11719632]

[8]

Whistler T, Jones JF, Unger ER, Vernon SD. Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects. BMC physiology. 2005 Mar 24:5(1):5 [PubMed PMID: 15790422]

[9]

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. Journal of clinical pathology. 2010 Feb:63(2):156-64. doi: 10.1136/jcp.2009.072561. Epub 2009 Dec 2 [PubMed PMID: 19955554]

[10]

. Myalgic encephalomyelitis: International Consensus Criteria. Journal of internal medicine. 2017 Oct:282(4):353. doi: 10.1111/joim.12658. Epub [PubMed PMID: 28929634]

Level 3 (low-level) evidence

[11]

DuBois RE, Seeley JK, Brus I, Sakamoto K, Ballow M, Harada S, Bechtold TA, Pearson G, Purtilo DT. Chronic mononucleosis syndrome. Southern medical journal. 1984 Nov:77(11):1376-82 [PubMed PMID: 6093268]

[12]

Jacobson SK, Daly JS, Thorne GM, McIntosh K. Chronic parvovirus B19 infection resulting in chronic fatigue syndrome: case history and review. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1997 Jun:24(6):1048-51 [PubMed PMID: 9195056]

Level 3 (low-level) evidence

[13]

Ortega-Hernandez OD, Shoenfeld Y. Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence? Annals of the New York Academy of Sciences. 2009 Sep:1173():600-9. doi: 10.1111/j.1749-6632.2009.04799.x. Epub [PubMed PMID: 19758205]

[14]

Manian FA. Simultaneous measurement of antibodies to Epstein-Barr virus, human herpesvirus 6, herpes simplex virus types 1 and 2, and 14 enteroviruses in chronic fatigue syndrome: is there evidence of activation of a nonspecific polyclonal immune response? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1994 Sep:19(3):448-53 [PubMed PMID: 7811864]

[15]

Loebel M, Strohschein K, Giannini C, Koelsch U, Bauer S, Doebis C, Thomas S, Unterwalder N, von Baehr V, Reinke P, Knops M, Hanitsch LG, Meisel C, Volk HD, Scheibenbogen C. Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. PloS one. 2014:9(1):e85387. doi: 10.1371/journal.pone.0085387. Epub 2014 Jan 15 [PubMed PMID: 24454857]

[16]

Loebel M, Eckey M, Sotzny F, Hahn E, Bauer S, Grabowski P, Zerweck J, Holenya P, Hanitsch LG, Wittke K, Borchmann P, Rüffer JU, Hiepe F, Ruprecht K, Behrends U, Meindl C, Volk HD, Reimer U, Scheibenbogen C. Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray. PloS one. 2017:12(6):e0179124. doi: 10.1371/journal.pone.0179124. Epub 2017 Jun 12 [PubMed PMID: 28604802]

[17]

Ablashi DV, Eastman HB, Owen CB, Roman MM, Friedman J, Zabriskie JB, Peterson DL, Pearson GR, Whitman JE. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2000 May:16(3):179-91 [PubMed PMID: 10738137]

[18]

Chapenko S, Krumina A, Kozireva S, Nora Z, Sultanova A, Viksna L, Murovska M. Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2006 Dec:37 Suppl 1():S47-51 [PubMed PMID: 17276369]

[19]

Frémont M, Metzger K, Rady H, Hulstaert J, De Meirleir K. Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients. In vivo (Athens, Greece). 2009 Mar-Apr:23(2):209-13 [PubMed PMID: 19414405]

[20]

Aoki R, Kobayashi N, Suzuki G, Kuratsune H, Shimada K, Oka N, Takahashi M, Yamadera W, Iwashita M, Tokuno S, Nibuya M, Tanichi M, Mukai Y, Mitani K, Kondo K, Ito H, Nakayama K. Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue. Biochemical and biophysical research communications. 2016 Sep 9:478(1):424-430. doi: 10.1016/j.bbrc.2016.07.010. Epub 2016 Jul 7 [PubMed PMID: 27396623]

[21]

Kerr JR. The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmune disease. Journal of clinical pathology. 2016 Apr:69(4):279-91. doi: 10.1136/jclinpath-2015-203455. Epub 2015 Dec 7 [PubMed PMID: 26644521]

[22]

Kerr JR, Barah F, Mattey DL, Laing I, Hopkins SJ, Hutchinson IV, Tyrrell DAJ. Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. The Journal of general virology. 2001 Dec:82(Pt 12):3011-3019. doi: 10.1099/0022-1317-82-12-3011. Epub [PubMed PMID: 11714978]

[23]

Barker E, Fujimura SF, Fadem MB, Landay AL, Levy JA. Immunologic abnormalities associated with chronic fatigue syndrome. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1994 Jan:18 Suppl 1():S136-41 [PubMed PMID: 8148441]

[24]

Bradley AS, Ford B, Bansal AS. Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls. Clinical and experimental immunology. 2013 Apr:172(1):73-80. doi: 10.1111/cei.12043. Epub [PubMed PMID: 23480187]

[25]

Mensah F, Bansal A, Berkovitz S, Sharma A, Reddy V, Leandro MJ, Cambridge G. Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional study. Clinical and experimental immunology. 2016 May:184(2):237-47. doi: 10.1111/cei.12749. Epub 2016 Feb 22 [PubMed PMID: 26646713]

Level 2 (mid-level) evidence

[26]

Guenther S, Loebel M, Mooslechner AA, Knops M, Hanitsch LG, Grabowski P, Wittke K, Meisel C, Unterwalder N, Volk HD, Scheibenbogen C. Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome. Human immunology. 2015 Oct:76(10):729-35. doi: 10.1016/j.humimm.2015.09.028. Epub 2015 Sep 30 [PubMed PMID: 26429318]

[27]

Löbel M, Mooslechner AA, Bauer S, Günther S, Letsch A, Hanitsch LG, Grabowski P, Meisel C, Volk HD, Scheibenbogen C. Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome. Journal of translational medicine. 2015 Aug 14:13():264. doi: 10.1186/s12967-015-0628-4. Epub 2015 Aug 14 [PubMed PMID: 26272340]

[28]

Konstantinov K, von Mikecz A, Buchwald D, Jones J, Gerace L, Tan EM. Autoantibodies to nuclear envelope antigens in chronic fatigue syndrome. The Journal of clinical investigation. 1996 Oct 15:98(8):1888-96 [PubMed PMID: 8878441]

[29]

Nishikai M, Tomomatsu S, Hankins RW, Takagi S, Miyachi K, Kosaka S, Akiya K. Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology (Oxford, England). 2001 Jul:40(7):806-10 [PubMed PMID: 11477286]

[30]

Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, Meisel C, Reinke P, Volk HD, Fluge Ø, Mella O, Scheibenbogen C. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain, behavior, and immunity. 2016 Feb:52():32-39. doi: 10.1016/j.bbi.2015.09.013. Epub 2015 Sep 21 [PubMed PMID: 26399744]

[31]

von Mikecz A, Konstantinov K, Buchwald DS, Gerace L, Tan EM. High frequency of autoantibodies to insoluble cellular antigens in patients with chronic fatigue syndrome. Arthritis and rheumatism. 1997 Feb:40(2):295-305 [PubMed PMID: 9041942]

[32]

Richman JA, Flaherty JA, Rospenda KM. Chronic fatigue syndrome: have flawed assumptions been derived from treatment-based studies? American journal of public health. 1994 Feb:84(2):282-4 [PubMed PMID: 8296954]

[33]

Steele L, Dobbins JG, Fukuda K, Reyes M, Randall B, Koppelman M, Reeves WC. The epidemiology of chronic fatigue in San Francisco. The American journal of medicine. 1998 Sep 28:105(3A):83S-90S [PubMed PMID: 9790487]

[34]

Fukuda K, Dobbins JG, Wilson LJ, Dunn RA, Wilcox K, Smallwood D. An epidemiologic study of fatigue with relevance for the chronic fatigue syndrome. Journal of psychiatric research. 1997 Jan-Feb:31(1):19-29 [PubMed PMID: 9201644]

[35]

Wessely S, Chalder T, Hirsch S, Wallace P, Wright D. The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. American journal of public health. 1997 Sep:87(9):1449-55 [PubMed PMID: 9314795]

[36]

Reyes M, Gary HE Jr, Dobbins JG, Randall B, Steele L, Fukuda K, Holmes GP, Connell DG, Mawle AC, Schmid DS, Stewart JA, Schonberger LB, Gunn WJ, Reeves WC. Surveillance for chronic fatigue syndrome--four U.S. cities, September 1989 through August 1993. MMWR. CDC surveillance summaries : Morbidity and mortality weekly report. CDC surveillance summaries. 1997 Feb 21:46(2):1-13 [PubMed PMID: 12412768]

[37]

Buchwald D, Umali P, Umali J, Kith P, Pearlman T, Komaroff AL. Chronic fatigue and the chronic fatigue syndrome: prevalence in a Pacific Northwest health care system. Annals of internal medicine. 1995 Jul 15:123(2):81-8 [PubMed PMID: 7778839]

[38]

Lawrie SM, Pelosi AJ. Chronic fatigue syndrome in the community. Prevalence and associations. The British journal of psychiatry : the journal of mental science. 1995 Jun:166(6):793-7 [PubMed PMID: 7663830]

[39]

Bierl C, Nisenbaum R, Hoaglin DC, Randall B, Jones AB, Unger ER, Reeves WC. Regional distribution of fatiguing illnesses in the United States: a pilot study. Population health metrics. 2004 Feb 4:2(1):1 [PubMed PMID: 14761250]

Level 3 (low-level) evidence

[40]

Vincent A, Brimmer DJ, Whipple MO, Jones JF, Boneva R, Lahr BD, Maloney E, St Sauver JL, Reeves WC. Prevalence, incidence, and classification of chronic fatigue syndrome in Olmsted County, Minnesota, as estimated using the Rochester Epidemiology Project. Mayo Clinic proceedings. 2012 Dec:87(12):1145-52. doi: 10.1016/j.mayocp.2012.08.015. Epub 2012 Nov 8 [PubMed PMID: 23140977]

[41]

Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Archives of internal medicine. 1999 Oct 11:159(18):2129-37 [PubMed PMID: 10527290]

[42]

Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G. Immunological aspects of chronic fatigue syndrome. Autoimmunity reviews. 2009 Feb:8(4):287-91. doi: 10.1016/j.autrev.2008.08.003. Epub 2008 Sep 16 [PubMed PMID: 18801465]

[42]

Lorusso L,Mikhaylova SV,Capelli E,Ferrari D,Ngonga GK,Ricevuti G, Immunological aspects of chronic fatigue syndrome. Autoimmunity reviews. 2009 Feb [PubMed PMID: 18801465]

[43]

Marshall-Gradisnik S, Huth T, Chacko A, Johnston S, Smith P, Staines D. Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome. The application of clinical genetics. 2016:9():39-47. doi: 10.2147/TACG.S99405. Epub 2016 Mar 31 [PubMed PMID: 27099524]

[44]

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 biology & medicine. 2005 Sep 1:39(5):584-9 [PubMed PMID: 16085177]

[45]

Kennedy G, Khan F, Hill A, Underwood C, Belch JJ. Biochemical and vascular aspects of pediatric chronic fatigue syndrome. Archives of pediatrics & adolescent medicine. 2010 Sep:164(9):817-23. doi: 10.1001/archpediatrics.2010.157. Epub [PubMed PMID: 20819963]

[46]

Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Current opinion in psychiatry. 2009 Jan:22(1):75-83 [PubMed PMID: 19127706]

Level 3 (low-level) evidence

[47]

Morris G, Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metabolic brain disease. 2014 Mar:29(1):19-36. doi: 10.1007/s11011-013-9435-x. Epub 2013 Sep 10 [PubMed PMID: 24557875]

[48]

Schoeman EM, Van Der Westhuizen FH, Erasmus E, van Dyk E, Knowles CV, Al-Ali S, Ng WF, Taylor RW, Newton JL, Elson JL. Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome. BMC medical genetics. 2017 Mar 16:18(1):29. doi: 10.1186/s12881-017-0387-6. Epub 2017 Mar 16 [PubMed PMID: 28302057]

[49]

Billing-Ross P, Germain A, Ye K, Keinan A, Gu Z, Hanson MR. Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. Journal of translational medicine. 2016 Jan 20:14():19. doi: 10.1186/s12967-016-0771-6. Epub 2016 Jan 20 [PubMed PMID: 26791940]

[50]

Finsterer J, Zarrouk-Mahjoub S. Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms? Journal of translational medicine. 2016 Jun 18:14(1):182. doi: 10.1186/s12967-016-0939-0. Epub 2016 Jun 18 [PubMed PMID: 27317438]

[51]

Nijs J, De Meirleir K. Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome. In vivo (Athens, Greece). 2005 Nov-Dec:19(6):1013-21 [PubMed PMID: 16277015]

[52]

Michel T, Poli A, Cuapio A, Briquemont B, Iserentant G, Ollert M, Zimmer J. Human CD56bright NK Cells: An Update. Journal of immunology (Baltimore, Md. : 1950). 2016 Apr 1:196(7):2923-31. doi: 10.4049/jimmunol.1502570. Epub [PubMed PMID: 26994304]

[53]

Poli A, Michel T, Thérésine M, Andrès E, Hentges F, Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset. Immunology. 2009 Apr:126(4):458-65. doi: 10.1111/j.1365-2567.2008.03027.x. Epub [PubMed PMID: 19278419]

[54]

Brenu EW, Huth TK, Hardcastle SL, Fuller K, Kaur M, Johnston S, Ramos SB, Staines DR, Marshall-Gradisnik SM. Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis. International immunology. 2014 Apr:26(4):233-42. doi: 10.1093/intimm/dxt068. Epub 2013 Dec 16 [PubMed PMID: 24343819]

[55]

Maes M, Twisk FN, Kubera M, Ringel K, Leunis JC, Geffard M. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. Journal of affective disorders. 2012 Feb:136(3):909-17. doi: 10.1016/j.jad.2011.09.010. Epub 2011 Oct 2 [PubMed PMID: 21967891]

[56]

Maes M, Mihaylova I, Leunis JC. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. Journal of affective disorders. 2007 Apr:99(1-3):237-40 [PubMed PMID: 17007934]

[57]

Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M, Scheibenbogen C, European Network on ME/CFS (EUROMENE). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease. Autoimmunity reviews. 2018 Jun:17(6):601-609. doi: 10.1016/j.autrev.2018.01.009. Epub 2018 Apr 7 [PubMed PMID: 29635081]

[58]

Ortega-Hernandez OD, Cuccia M, Bozzini S, Bassi N, Moscavitch S, Diaz-Gallo LM, Blank M, Agmon-Levin N, Shoenfeld Y. Autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen class II alleles in chronic fatigue syndrome: are they associated with age at onset and specific symptoms? Annals of the New York Academy of Sciences. 2009 Sep:1173():589-99. doi: 10.1111/j.1749-6632.2009.04802.x. Epub [PubMed PMID: 19758204]

[59]

Reynolds GK, Lewis DP, Richardson AM, Lidbury BA. Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. Journal of internal medicine. 2014 Apr:275(4):409-17. doi: 10.1111/joim.12161. Epub 2013 Nov 29 [PubMed PMID: 24206536]

[60]

Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, Kataoka Y, Shiomi S, Yamaguti K, Inaba M, Kuratsune H, Watanabe Y. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2014 Jun:55(6):945-50. doi: 10.2967/jnumed.113.131045. Epub 2014 Mar 24 [PubMed PMID: 24665088]

[61]

Chen MK, Guilarte TR. Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacology & therapeutics. 2008 Apr:118(1):1-17. doi: 10.1016/j.pharmthera.2007.12.004. Epub 2008 Feb 9 [PubMed PMID: 18374421]

[62]

Glassford JA. The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Frontiers in physiology. 2017:8():88. doi: 10.3389/fphys.2017.00088. Epub 2017 Feb 17 [PubMed PMID: 28261110]

[63]

Svahn KS, Göransson U, Chryssanthou E, Olsen B, Sjölin J, Strömstedt AA. Induction of gliotoxin secretion in Aspergillus fumigatus by bacteria-associated molecules. PloS one. 2014:9(4):e93685. doi: 10.1371/journal.pone.0093685. Epub 2014 Apr 4 [PubMed PMID: 24705440]

[64]

Yamashita M, Yamamoto T. Tryptophan circuit in fatigue: From blood to brain and cognition. Brain research. 2017 Nov 15:1675():116-126. doi: 10.1016/j.brainres.2017.09.002. Epub 2017 Sep 8 [PubMed PMID: 28893581]

[65]

Cotel F, Exley R, Cragg SJ, Perrier JF. Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation. Proceedings of the National Academy of Sciences of the United States of America. 2013 Mar 19:110(12):4774-9. doi: 10.1073/pnas.1216150110. Epub 2013 Mar 4 [PubMed PMID: 23487756]

[66]

Liu JZ, Yao B, Siemionow V, Sahgal V, Wang X, Sun J, Yue GH. Fatigue induces greater brain signal reduction during sustained than preparation phase of maximal voluntary contraction. Brain research. 2005 Sep 28:1057(1-2):113-26 [PubMed PMID: 16129419]

[67]

Hall DL, Lattie EG, Antoni MH, Fletcher MA, Czaja S, Perdomo D, Klimas NG. Stress management skills, cortisol awakening response, and post-exertional malaise in Chronic Fatigue Syndrome. Psychoneuroendocrinology. 2014 Nov:49():26-31. doi: 10.1016/j.psyneuen.2014.06.021. Epub 2014 Jul 6 [PubMed PMID: 25049069]

[68]

Wallis A, Ball M, McKechnie S, Butt H, Lewis DP, Bruck D. Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review. Journal of translational medicine. 2017 Jun 7:15(1):129. doi: 10.1186/s12967-017-1229-1. Epub 2017 Jun 7 [PubMed PMID: 28592308]

Level 1 (high-level) evidence

[69]

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. Journal of translational medicine. 2010 Oct 11:8():93. doi: 10.1186/1479-5876-8-93. Epub 2010 Oct 11 [PubMed PMID: 20937116]

[70]

MacDonald KL, Osterholm MT, LeDell KH, White KE, Schenck CH, Chao CC, Persing DH, Johnson RC, Barker JM, Peterson PK. A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome. The American journal of medicine. 1996 May:100(5):548-54 [PubMed PMID: 8644768]

Level 2 (mid-level) evidence

[71]

Salit IE. Precipitating factors for the chronic fatigue syndrome. Journal of psychiatric research. 1997 Jan-Feb:31(1):59-65 [PubMed PMID: 9201648]

[72]

Rowe PC, Underhill RA, Friedman KJ, Gurwitt A, Medow MS, Schwartz MS, Speight N, Stewart JM, Vallings R, Rowe KS. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer. Frontiers in pediatrics. 2017:5():121. doi: 10.3389/fped.2017.00121. Epub 2017 Jun 19 [PubMed PMID: 28674681]

[73]

Clauw DJ. Perspectives on fatigue from the study of chronic fatigue syndrome and related conditions. PM & R : the journal of injury, function, and rehabilitation. 2010 May:2(5):414-30. doi: 10.1016/j.pmrj.2010.04.010. Epub [PubMed PMID: 20656623]

Level 3 (low-level) evidence

[74]

Cockshell SJ, Mathias JL. Cognitive functioning in chronic fatigue syndrome: a meta-analysis. Psychological medicine. 2010 Aug:40(8):1253-67. doi: 10.1017/S0033291709992054. Epub 2010 Jan 5 [PubMed PMID: 20047703]

Level 1 (high-level) evidence

[75]

Bested AC, Marshall LM. Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians. Reviews on environmental health. 2015:30(4):223-49. doi: 10.1515/reveh-2015-0026. Epub [PubMed PMID: 26613325]

[76]

Komaroff AL, Fagioli LR, Geiger AM, Doolittle TH, Lee J, Kornish RJ, Gleit MA, Guerriero RT. An examination of the working case definition of chronic fatigue syndrome. The American journal of medicine. 1996 Jan:100(1):56-64 [PubMed PMID: 8579088]

Level 3 (low-level) evidence

[77]

Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ. A report--chronic fatigue syndrome: guidelines for research. Journal of the Royal Society of Medicine. 1991 Feb:84(2):118-21 [PubMed PMID: 1999813]

[78]

Afari N, Buchwald D. Chronic fatigue syndrome: a review. The American journal of psychiatry. 2003 Feb:160(2):221-36 [PubMed PMID: 12562565]

[79]

Bombardier CH, Buchwald D. Chronic fatigue, chronic fatigue syndrome, and fibromyalgia. Disability and health-care use. Medical care. 1996 Sep:34(9):924-30 [PubMed PMID: 8792781]

[80]

White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M, PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet (London, England). 2011 Mar 5:377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18 [PubMed PMID: 21334061]

Level 1 (high-level) evidence

[81]

Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. The Cochrane database of systematic reviews. 2016 Jun 24:(6):CD003200. doi: 10.1002/14651858.CD003200.pub5. Epub 2016 Jun 24 [PubMed PMID: 27339435]

Level 1 (high-level) evidence

[82]

Sharpe M, Goldsmith KA, Johnson AL, Chalder T, Walker J, White PD. Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial. The lancet. Psychiatry. 2015 Dec:2(12):1067-74. doi: 10.1016/S2215-0366(15)00317-X. Epub 2015 Oct 28 [PubMed PMID: 26521770]

[83]

Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Annals of internal medicine. 1994 Dec 15:121(12):953-9 [PubMed PMID: 7978722]

[84]

Clayton EW. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. JAMA. 2015 Mar 17:313(11):1101-2. doi: 10.1001/jama.2015.1346. Epub [PubMed PMID: 25668027]

[85]

Jason LA, Sunnquist M. The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions. Frontiers in pediatrics. 2018:6():330. doi: 10.3389/fped.2018.00330. Epub 2018 Nov 6 [PubMed PMID: 30460215]

[86]

Wagner D, Nisenbaum R, Heim C, Jones JF, Unger ER, Reeves WC. Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome. Population health metrics. 2005 Jul 22:3():8 [PubMed PMID: 16042777]

[87]

Baker R, Shaw EJ. Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): summary of NICE guidance. BMJ (Clinical research ed.). 2007 Sep 1:335(7617):446-8 [PubMed PMID: 17762037]

[88]

Wilshire CE, Kindlon T, Courtney R, Matthees A, Tuller D, Geraghty K, Levin B. Rethinking the treatment of chronic fatigue syndrome-a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC psychology. 2018 Mar 22:6(1):6. doi: 10.1186/s40359-018-0218-3. Epub 2018 Mar 22 [PubMed PMID: 29562932]

[89]

National Collaborating Centre for Primary Care (UK). Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy): Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children. 2007 Aug:(): [PubMed PMID: 21563329]

[90]

O'Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health technology assessment (Winchester, England). 2006 Oct:10(37):iii-iv, ix-x, 1-121 [PubMed PMID: 17014748]

Level 1 (high-level) evidence

[91]

Deale A, Husain K, Chalder T, Wessely S. Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. The American journal of psychiatry. 2001 Dec:158(12):2038-42 [PubMed PMID: 11729022]

[92]

Vos-Vromans DC, Smeets RJ, Huijnen IP, Köke AJ, Hitters WM, Rijnders LJ, Pont M, Winkens B, Knottnerus JA. Multidisciplinary rehabilitation treatment versus cognitive behavioural therapy for patients with chronic fatigue syndrome: a randomized controlled trial. Journal of internal medicine. 2016 Mar:279(3):268-82. doi: 10.1111/joim.12402. Epub 2015 Aug 26 [PubMed PMID: 26306716]

Level 1 (high-level) evidence

[93]

Nijhof SL, Bleijenberg G, Uiterwaal CS, Kimpen JL, van de Putte EM. Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial. Lancet (London, England). 2012 Apr 14:379(9824):1412-8. doi: 10.1016/S0140-6736(12)60025-7. Epub 2012 Mar 3 [PubMed PMID: 22385683]

Level 1 (high-level) evidence

[94]

Powell P, Bentall RP, Nye FJ, Edwards RH. Patient education to encourage graded exercise in chronic fatigue syndrome. 2-year follow-up of randomised controlled trial. The British journal of psychiatry : the journal of mental science. 2004 Feb:184():142-6 [PubMed PMID: 14754826]

Level 1 (high-level) evidence

[95]

Moss-Morris R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. Journal of health psychology. 2005 Mar:10(2):245-59 [PubMed PMID: 15723894]

Level 1 (high-level) evidence

[96]

Li SH, Sandler CX, Casson SM, Cassar J, Bogg T, Lloyd AR, Barry BK. Randomised controlled trial of online continuing education for health professionals to improve the management of chronic fatigue syndrome: a study protocol. BMJ open. 2017 May 10:7(5):e014133. doi: 10.1136/bmjopen-2016-014133. Epub 2017 May 10 [PubMed PMID: 28495811]

Level 1 (high-level) evidence

[97]

Castro-Marrero J, Sáez-Francàs N, Santillo D, Alegre J. Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome. British journal of pharmacology. 2017 Mar:174(5):345-369. doi: 10.1111/bph.13702. Epub 2017 Feb 1 [PubMed PMID: 28052319]

[98]

Theoharides TC, Asadi S, Weng Z, Zhang B. Serotonin-selective reuptake inhibitors and nonsteroidal anti-inflammatory drugs--important considerations of adverse interactions especially for the treatment of myalgic encephalomyelitis/chronic fatigue syndrome. Journal of clinical psychopharmacology. 2011 Aug:31(4):403-5. doi: 10.1097/JCP.0b013e318225848c. Epub [PubMed PMID: 21694612]

[99]

Degenhardt L, Gisev N, Cama E, Nielsen S, Larance B, Bruno R. The extent and correlates of community-based pharmaceutical opioid utilisation in Australia. Pharmacoepidemiology and drug safety. 2016 May:25(5):521-38. doi: 10.1002/pds.3931. Epub 2016 Jan 19 [PubMed PMID: 26781123]

[100]

Clemons A, Vasiadi M, Kempuraj D, Kourelis T, Vandoros G, Theoharides TC. Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrome. Journal of clinical psychopharmacology. 2011 Jun:31(3):385-7. doi: 10.1097/JCP.0b013e3182196e50. Epub [PubMed PMID: 21532369]

[101]

Sanders P, Korf J. Neuroaetiology of chronic fatigue syndrome: an overview. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. 2008:9(3):165-71 [PubMed PMID: 17853290]

Level 3 (low-level) evidence

[102]

Jason L, Benton M, Torres-Harding S, Muldowney K. The impact of energy modulation on physical functioning and fatigue severity among patients with ME/CFS. Patient education and counseling. 2009 Nov:77(2):237-41. doi: 10.1016/j.pec.2009.02.015. Epub 2009 Apr 8 [PubMed PMID: 19356884]

[103]

Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, Thompson C, Loveless M, Shapiro DE, Elsasser W. A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1994 Jan:18 Suppl 1():S88-95 [PubMed PMID: 8148460]

Level 1 (high-level) evidence

[104]

Brook MG, Bannister BA, Weir WR. Interferon-alpha therapy for patients with chronic fatigue syndrome. The Journal of infectious diseases. 1993 Sep:168(3):791-2 [PubMed PMID: 8354926]

[105]

Cleare AJ, Reid S, Chalder T, Hotopf M, Wessely S. Chronic fatigue syndrome. BMJ clinical evidence. 2015 Sep 28:2015():. pii: 1101. Epub 2015 Sep 28 [PubMed PMID: 26415100]

[106]

Chambers D, Bagnall AM, Hempel S, Forbes C. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. Journal of the Royal Society of Medicine. 2006 Oct:99(10):506-20 [PubMed PMID: 17021301]

Level 1 (high-level) evidence

[107]

Smith ME, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, Fu R, Nelson HD. Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. Annals of internal medicine. 2015 Jun 16:162(12):841-50. doi: 10.7326/M15-0114. Epub [PubMed PMID: 26075755]

Level 1 (high-level) evidence

[108]

Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Ramírez G. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA. 2001 Sep 19:286(11):1360-8 [PubMed PMID: 11560542]

Level 1 (high-level) evidence

[109]

Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PloS one. 2011:6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19 [PubMed PMID: 22039471]

Level 1 (high-level) evidence

[110]

Fluge Ø, Rekeland IG, Lien K, Thürmer H, Borchgrevink PC, Schäfer C, Sørland K, Aßmus J, Ktoridou-Valen I, Herder I, Gotaas ME, Kvammen Ø, Baranowska KA, Bohnen LMLJ, Martinsen SS, Lonar AE, Solvang AH, Gya AES, Bruland O, Risa K, Alme K, Dahl O, Mella O. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Annals of internal medicine. 2019 May 7:170(9):585-593. doi: 10.7326/M18-1451. Epub 2019 Apr 2 [PubMed PMID: 30934066]

Level 1 (high-level) evidence

[111]

Brüssow H. Biome engineering-2020. Microbial biotechnology. 2016 Sep:9(5):553-63. doi: 10.1111/1751-7915.12391. Epub 2016 Jul 29 [PubMed PMID: 27471167]

[112]

Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology. 2013 Nov:145(5):946-53. doi: 10.1053/j.gastro.2013.08.058. Epub 2013 Sep 7 [PubMed PMID: 24018052]

[113]

Bibbò S, Ianiro G, Gasbarrini A, Cammarota G. Fecal microbiota transplantation: past, present and future perspectives. Minerva gastroenterologica e dietologica. 2017 Dec:63(4):420-430. doi: 10.23736/S1121-421X.17.02374-1. Epub [PubMed PMID: 28927251]

Level 3 (low-level) evidence

[114]

Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2016 Jun 23:4(1):30. doi: 10.1186/s40168-016-0171-4. Epub 2016 Jun 23 [PubMed PMID: 27338587]

[115]

Frémont M, Coomans D, Massart S, De Meirleir K. High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe. 2013 Aug:22():50-6. doi: 10.1016/j.anaerobe.2013.06.002. Epub 2013 Jun 19 [PubMed PMID: 23791918]

[116]

Navaneetharaja N, Griffiths V, Wileman T, Carding SR. A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)? Journal of clinical medicine. 2016 Jun 6:5(6):. doi: 10.3390/jcm5060055. Epub 2016 Jun 6 [PubMed PMID: 27275835]

[117]

Wallis A, Butt H, Ball M, Lewis DP, Bruck D. Support for the microgenderome invites enquiry into sex differences. Gut microbes. 2017 Jan 2:8(1):46-52. doi: 10.1080/19490976.2016.1256524. Epub 2016 Nov 3 [PubMed PMID: 27808584]

[118]

Guo HJ, Sapra A. Instrumental Activity of Daily Living. StatPearls. 2024 Jan:(): [PubMed PMID: 31985920]

[119]

Treisman R. Identification and purification of a polypeptide that binds to the c-fos serum response element. The EMBO journal. 1987 Sep:6(9):2711-7 [PubMed PMID: 3119326]

[120]

Lee HM, Sugino H, Nishimoto N. Cytokine networks in systemic lupus erythematosus. Journal of biomedicine & biotechnology. 2010:2010():676284. doi: 10.1155/2010/676284. Epub 2010 Apr 15 [PubMed PMID: 20414360]

[121]

Davis MC, Zautra AJ, Younger J, Motivala SJ, Attrep J, Irwin MR. Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: implications for fatigue. Brain, behavior, and immunity. 2008 Jan:22(1):24-32 [PubMed PMID: 17706915]

[122]

Harboe E, Tjensvoll AB, Vefring HK, Gøransson LG, Kvaløy JT, Omdal R. Fatigue in primary Sjögren's syndrome--a link to sickness behaviour in animals? Brain, behavior, and immunity. 2009 Nov:23(8):1104-8. doi: 10.1016/j.bbi.2009.06.151. Epub 2009 Jun 26 [PubMed PMID: 19560535]

Level 3 (low-level) evidence

[123]

Stadje R, Dornieden K, Baum E, Becker A, Biroga T, Bösner S, Haasenritter J, Keunecke C, Viniol A, Donner-Banzhoff N. The differential diagnosis of tiredness: a systematic review. BMC family practice. 2016 Oct 20:17(1):147 [PubMed PMID: 27765009]

Level 1 (high-level) evidence

[124]

Sekhon S, Patel J, Sapra A. Late-Life Depression. StatPearls. 2024 Jan:(): [PubMed PMID: 31855351]

[125]

Budh DP, Sapra A. Breast Cancer Screening. StatPearls. 2023 Jan:(): [PubMed PMID: 32310510]

[126]

Bower JE, Ganz PA, Irwin MR, Arevalo JM, Cole SW. Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Brain, behavior, and immunity. 2011 Jan:25(1):147-50. doi: 10.1016/j.bbi.2010.09.010. Epub 2010 Sep 18 [PubMed PMID: 20854893]

[127]

Kwak SM, Choi YS, Yoon HM, Kim DG, Song SH, Lee YJ, Yeom CH, Koh SJ, Park J, Lee MA, Suh SY. The relationship between interleukin-6, tumor necrosis factor-α, and fatigue in terminally ill cancer patients. Palliative medicine. 2012 Apr:26(3):275-82. doi: 10.1177/0269216311406991. Epub 2011 Aug 1 [PubMed PMID: 21807751]

[128]

Thornton LM, Andersen BL, Blakely WP. The pain, depression, and fatigue symptom cluster in advanced breast cancer: covariation with the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Health psychology : official journal of the Division of Health Psychology, American Psychological Association. 2010 May:29(3):333-7. doi: 10.1037/a0018836. Epub [PubMed PMID: 20496988]

[129]

Bower JE, Ganz PA, Tao ML, Hu W, Belin TR, Sepah S, Cole S, Aziz N. Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009 Sep 1:15(17):5534-40. doi: 10.1158/1078-0432.CCR-08-2584. Epub 2009 Aug 25 [PubMed PMID: 19706826]

[130]

Jelsness-Jørgensen LP, Bernklev T, Henriksen M, Torp R, Moum BA. Chronic fatigue is more prevalent in patients with inflammatory bowel disease than in healthy controls. Inflammatory bowel diseases. 2011 Jul:17(7):1564-72. doi: 10.1002/ibd.21530. Epub 2010 Nov 8 [PubMed PMID: 21674713]

[131]

Gold SM, Krüger S, Ziegler KJ, Krieger T, Schulz KH, Otte C, Heesen C. Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. Journal of neurology, neurosurgery, and psychiatry. 2011 Jul:82(7):814-8. doi: 10.1136/jnnp.2010.230029. Epub 2011 Feb 4 [PubMed PMID: 21296901]

[132]

Sapra A, Malik A, Bhandari P. Vital Sign Assessment. StatPearls. 2024 Jan:(): [PubMed PMID: 31985994]

[133]

Al-shair K, Kolsum U, Dockry R, Morris J, Singh D, Vestbo J. Biomarkers of systemic inflammation and depression and fatigue in moderate clinically stable COPD. Respiratory research. 2011 Jan 5:12(1):3. doi: 10.1186/1465-9921-12-3. Epub 2011 Jan 5 [PubMed PMID: 21208443]

[134]

Mills PJ, Kim JH, Bardwell W, Hong S, Dimsdale JE. Predictors of fatigue in obstructive sleep apnea. Sleep & breathing = Schlaf & Atmung. 2008 Nov:12(4):397-9. doi: 10.1007/s11325-008-0192-8. Epub 2008 May 31 [PubMed PMID: 18516635]

[135]

Nyland M,Naess H,Birkeland JS,Nyland H, Longitudinal follow-up of employment status in patients with chronic fatigue syndrome after mononucleosis. BMJ open. 2014 Nov 26 [PubMed PMID: 25428629]

[136]

Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. QJM : monthly journal of the Association of Physicians. 1997 Mar:90(3):223-33 [PubMed PMID: 9093600]

Level 1 (high-level) evidence

[137]

Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occupational medicine (Oxford, England). 2005 Jan:55(1):20-31 [PubMed PMID: 15699087]

Level 1 (high-level) evidence