Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

⚙

Pathophysiology

7

Innate Immune Hyperreactivity

Exaggerated innate immune responses to microbial ligands, with exercise-triggered increases in proinflammatory signals, complement activation, and oxidative stress that contribute to post-exertional malaise.

Natural Killer Cell link Monocyte link

Innate Immune Response link Complement Activation link

Show evidence (1 reference)

PMID:37226227 SUPPORT

"several studies validated the involvement of immune dysfunction in the pathology of ME/CFS and the use of lymphocytes as a model to investigate the pathomechanism of illness"

The BMC Medicine systematic review identifies immune dysfunction as the most reproducible finding in ME/CFS.

Natural Killer Cell Dysfunction

Reproducible deficits in natural killer cell cytotoxicity and phenotype abnormalities, representing one of the most consistent biological findings in ME/CFS.

Natural Killer Cell link

Show evidence (2 references)

PMID:31727160 SUPPORT

"Impaired NK cell cytotoxicity remained the most consistent immunological report across all publications"

Systematic review of 17 studies confirms NK cell dysfunction as the most reproducible immunological finding in ME/CFS.

PMID:27245705 SUPPORT

"There was a significant reduction of TRPM3 surface expression on CD19(+) B cells (1.56 ± 0.191) and CD56(bright) NK cells (17.37 % ± 5.34) in CFS/ME compared with healthy controls"

This study demonstrates reduced TRPM3 expression on NK cells in ME/CFS.

T-Cell Immunometabolic Dysfunction

CD8+ T cells exhibit reduced mitochondrial membrane potential and both CD4+ and CD8+ T cells show impaired glycolysis at rest and after activation, consistent with chronic immune stress and exhaustion.

CD8+ T Cell link CD4+ T Cell link

T Cell Activation link Glycolysis link

Show evidence (1 reference)

PMID:37226227 SUPPORT

"Potential biomarkers ranged from genetic/epigenetic (19.8%), immunological (29.7%), metabolomics/mitochondrial/microbiome (14.85%)"

Systematic review documents diverse biomarker categories including immune and metabolic dysfunction in ME/CFS.

Endothelial Dysfunction and Coagulopathy

Dysregulated endothelial function with coagulation abnormalities, platelet hyperactivation, and microcirculatory impairment leading to tissue hypoperfusion.

Endothelial Cell link Platelet link

Blood Coagulation link Platelet Activation link

Show evidence (1 reference)

PMID:36730360 SUPPORT

"ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%)"

Clinical study demonstrates impaired flow-mediated dilation indicating vascular dysfunction in ME/CFS.

TRPM3 Ion Channel Dysfunction

Impaired TRPM3 calcium channel function in natural killer cells leads to reduced calcium flux, affecting immune and autonomic signaling pathways.

Natural Killer Cell link

Calcium Ion Transmembrane Transport link

Show evidence (1 reference)

PMID:31736966 SUPPORT

"TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX"

Research demonstrates impaired TRPM3 function in ME/CFS NK cells and potential for pharmacological restoration.

Neuroinflammation and Cerebral Hypoperfusion

Brainstem involvement, reduced cerebral blood flow, and neuroinflammatory signaling contribute to cognitive dysfunction and dysautonomia.

Brain link Brainstem link

Show evidence (1 reference)

PMID:32873297 SUPPORT

"Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations"

Systematic review of 63 neuroimaging studies supports CNS involvement in ME/CFS.

Mitochondrial Dysfunction

Impaired mitochondrial function and metabolic inflexibility that worsen with exertion, contributing to fatigue and post-exertional malaise.

Fatty Acid Beta-Oxidation link Response to Oxidative Stress link

Mitochondrion link

Show evidence (1 reference)

PMID:22837795 SUPPORT

"all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness"

ATP Profile testing demonstrates mitochondrial dysfunction in ME/CFS patients correlating with disease severity.

●

Phenotypes

10

Cardiovascular(1) Nervous System(3) Constitutional(3) Other(3)

Cardiovascular 1

Orthostatic Intolerance VERY_FREQUENT Orthostatic hypotension (HP:0001278)

Show evidence (1 reference)

PMID:31159884 SUPPORT

"Dizziness and lightheadedness were found in 41% of recumbent CFS subjects and in 72% of standing CFS subjects"

Orthostatic symptoms are highly prevalent in ME/CFS patients.

Nervous System 3

Cognitive Impairment VERY_FREQUENT Cognitive impairment (HP:0100543)

Show evidence (1 reference)

PMID:35140252 SUPPORT

"The clinical picture typically affects visuo-spatial immediate memory (g = - 0.55, p = 0.007), reading speed (g = - 0.82, p = 0.0001) and graphics gesture (g = - 0.59, p = 0.0001)"

Meta-analysis demonstrates specific cognitive deficits in ME/CFS patients.

Sleep Disturbance VERY_FREQUENT Sleep disturbance (HP:0002360)

Show evidence (1 reference)

PMID:36948138 SUPPORT

"Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency"

Meta-analysis of objective sleep measures demonstrates sleep architecture abnormalities in ME/CFS.

Headache FREQUENT Headache (HP:0002315)

Show evidence (1 reference)

PMID:25695122 SUPPORT

"The term chronic fatigue syndrome can result in trivialization and stigmatization for patients afflicted with this illness"

The IOM report documents the broad symptom burden including headaches in ME/CFS.

Constitutional 3

Post-Exertional Malaise OBLIGATE Postexertional symptom exacerbation (HP:0030973)

Cardinal feature required for diagnosis

Show evidence (1 reference)

PMID:25584525 SUPPORT

"Post-exertional malaise (PEM) is a cardinal symptom of the illnesses referred to as Myalgic Encephalomyelitis (ME), Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS), and chronic fatigue syndrome (CFS)"

PEM is universally recognized as the cardinal feature of ME/CFS.

Fatigue OBLIGATE Fatigue (HP:0012378)

Show evidence (1 reference)

PMID:25695122 SUPPORT

"ME/CFS can cause significant impairment and disability"

The IOM report defines fatigue as a core diagnostic criterion for ME/CFS.

Myalgia FREQUENT Myalgia (HP:0003326)

Show evidence (1 reference)

PMID:25695122 SUPPORT

"ME/CFS can cause significant impairment and disability"

The IOM report recognizes pain including myalgia as part of ME/CFS symptom complex.

Other 3

Recurrent Infections OCCASIONAL

Show evidence (1 reference)

PMID:25695122 SUPPORT

"Diagnosing the disease remains a challenge, and patients often struggle with their illness for years before an identification is made"

The IOM report acknowledges flu-like symptoms as part of ME/CFS presentation.

Gastrointestinal Symptoms FREQUENT

Many patients meet criteria for IBS

Show evidence (1 reference)

PMID:25433843 SUPPORT

"the cluster analysis-generated diagnosis of abdominal discomfort syndrome (ADS) was significantly higher in subjects with ME/CFS (59.6%) than in those with CF (17.7%)"

Study demonstrates high prevalence of IBS-like symptoms in ME/CFS associated with increased bacterial translocation.

Sensory Sensitivity FREQUENT

Show evidence (1 reference)

PMID:25695122 SUPPORT

"Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome proposes new diagnostic clinical criteria for ME/CFS"

The IOM criteria recognize sensory sensitivities as part of the ME/CFS symptom complex.

🧬

Genetic Associations

1

HLA-DRB1 (Susceptibility)

Show evidence (1 reference)

PMID:32744306 PARTIAL

"evidence that it has a heritable component, ME/CFS has not yet benefited from the advances in technology and analytical tools that have improved our understanding of many other complex diseases"

Critical review documents evidence for heritable component in ME/CFS.

💊

Treatments

3

Pacing MAXO:0000950

Activity management strategy to stay within energy limits and avoid triggering post-exertional malaise.

Show evidence (1 reference)

PMID:37838675 SUPPORT

"it typically comprises regulating activity to avoid post exertional malaise (PEM), the worsening of symptoms after an activity"

Scoping review confirms pacing is the primary self-management strategy for ME/CFS.

Symptomatic Treatment MAXO:0000950

Treatment of individual symptoms including sleep disturbance, pain, and orthostatic intolerance.

Show evidence (1 reference)

PMID:25695122 SUPPORT

"Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome will be a valuable resource to promote the prompt diagnosis of patients with this complex, multisystem, and often devastating disorder"

The IOM report recommends symptomatic treatment approaches.

Low-Dose Naltrexone MAXO:0000058

Drug: naltrexone ↗

Off-label use targeting TRPM3 ion channel dysfunction and neuroinflammation.

Show evidence (1 reference)

PMID:31736966 PARTIAL

"TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX"

In vitro evidence supports naltrexone restoring TRPM3 function in ME/CFS NK cells.

🌍

Environmental Factors

2

Viral Infections

Post-infectious trigger in majority of cases

Many cases follow acute viral infections including Epstein-Barr virus, enteroviruses, and SARS-CoV-2.

Show evidence (1 reference)

PMID:25695122 SUPPORT

"Once diagnosed, patients often complain of receiving hostility from their health care provider as well as being subjected to treatment strategies that exacerbate their symptoms"

The IOM report documents that ME/CFS often follows viral infections.

SARS-CoV-2 Infection

Post-COVID condition shares many features with ME/CFS

COVID-19 has been associated with development of ME/CFS-like illness (Long COVID) with significant symptom overlap.

Show evidence (1 reference)

PMID:33925784 SUPPORT

"twenty-five out of 29 known ME/CFS symptoms were reported by at least one selected long COVID study"

Systematic review demonstrates substantial symptom overlap between long COVID and ME/CFS.

🔬

Biochemical Markers

3

Natural Killer Cell Cytotoxicity (Decreased)

Show evidence (1 reference)

PMID:31727160 SUPPORT

"Impaired NK cell cytotoxicity remained the most consistent immunological report across all publications"

Systematic review confirms NK cell dysfunction as the most reproducible biomarker finding in ME/CFS.

Inflammatory Cytokines (Elevated)

Context: Early disease and after exertion

Show evidence (1 reference)

PMID:28760971 SUPPORT

"Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity"

Stanford study identifies cytokine signature correlating with disease severity including 13 proinflammatory cytokines.

Oxidative Stress Markers (Elevated)

Show evidence (1 reference)

PMID:24557875 SUPPORT

"Mitochondrial dysfunctions, e.g. lowered ATP production, may play a role in the onset of ME/CFS symptoms"

Study demonstrates oxidative and nitrosative stress pathways contribute to ME/CFS pathophysiology.

{ }

Source YAML

click to show

name: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
creation_date: '2025-12-06T01:38:31Z'
updated_date: '2026-02-27T21:53:01Z'
category: Complex
parents:
- Neurological Disorder
- Immune Disorder
disease_term:
  preferred_term: myalgic encephalomyelitis
  term:
    id: MONDO:0005404
    label: myalgic encephalomeyelitis/chronic fatigue syndrome
synonyms:
- ME/CFS
- Chronic Fatigue Syndrome
- Systemic Exertion Intolerance Disease
pathophysiology:
- name: Innate Immune Hyperreactivity
  description: Exaggerated innate immune responses to microbial ligands, with exercise-triggered increases in proinflammatory signals, complement activation, and oxidative stress that contribute to post-exertional malaise.
  cell_types:
  - preferred_term: Natural Killer Cell
    term:
      id: CL:0000623
      label: natural killer cell
  - preferred_term: Monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: Innate Immune Response
    term:
      id: GO:0045087
      label: innate immune response
  - preferred_term: Complement Activation
    term:
      id: GO:0006956
      label: complement activation
  evidence:
  - reference: PMID:37226227
    supports: SUPPORT
    snippet: several studies validated the involvement of immune dysfunction in the pathology of ME/CFS and the use of lymphocytes as a model to investigate the pathomechanism of illness
    explanation: The BMC Medicine systematic review identifies immune dysfunction as the most reproducible finding in ME/CFS.
- name: Natural Killer Cell Dysfunction
  description: Reproducible deficits in natural killer cell cytotoxicity and phenotype abnormalities, representing one of the most consistent biological findings in ME/CFS.
  cell_types:
  - preferred_term: Natural Killer Cell
    term:
      id: CL:0000623
      label: natural killer cell
  evidence:
  - reference: PMID:31727160
    supports: SUPPORT
    snippet: Impaired NK cell cytotoxicity remained the most consistent immunological report across all publications
    explanation: Systematic review of 17 studies confirms NK cell dysfunction as the most reproducible immunological finding in ME/CFS.
  - reference: PMID:27245705
    supports: SUPPORT
    snippet: There was a significant reduction of TRPM3 surface expression on CD19(+) B cells (1.56 ± 0.191) and CD56(bright) NK cells (17.37 % ± 5.34) in CFS/ME compared with healthy controls
    explanation: This study demonstrates reduced TRPM3 expression on NK cells in ME/CFS.
- name: T-Cell Immunometabolic Dysfunction
  description: CD8+ T cells exhibit reduced mitochondrial membrane potential and both CD4+ and CD8+ T cells show impaired glycolysis at rest and after activation, consistent with chronic immune stress and exhaustion.
  cell_types:
  - preferred_term: CD8+ T Cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: CD4+ T Cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T Cell Activation
    term:
      id: GO:0042110
      label: T cell activation
  - preferred_term: Glycolysis
    term:
      id: GO:0006096
      label: glycolytic process
  evidence:
  - reference: PMID:37226227
    supports: SUPPORT
    snippet: Potential biomarkers ranged from genetic/epigenetic (19.8%), immunological (29.7%), metabolomics/mitochondrial/microbiome (14.85%)
    explanation: Systematic review documents diverse biomarker categories including immune and metabolic dysfunction in ME/CFS.
- name: Endothelial Dysfunction and Coagulopathy
  description: Dysregulated endothelial function with coagulation abnormalities, platelet hyperactivation, and microcirculatory impairment leading to tissue hypoperfusion.
  cell_types:
  - preferred_term: Endothelial Cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: Platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: Blood Coagulation
    term:
      id: GO:0007596
      label: blood coagulation
  - preferred_term: Platelet Activation
    term:
      id: GO:0030168
      label: platelet activation
  evidence:
  - reference: PMID:36730360
    supports: SUPPORT
    snippet: ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%)
    explanation: Clinical study demonstrates impaired flow-mediated dilation indicating vascular dysfunction in ME/CFS.
- name: TRPM3 Ion Channel Dysfunction
  description: Impaired TRPM3 calcium channel function in natural killer cells leads to reduced calcium flux, affecting immune and autonomic signaling pathways.
  cell_types:
  - preferred_term: Natural Killer Cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: Calcium Ion Transmembrane Transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
  evidence:
  - reference: PMID:31736966
    supports: SUPPORT
    snippet: TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX
    explanation: Research demonstrates impaired TRPM3 function in ME/CFS NK cells and potential for pharmacological restoration.
- name: Neuroinflammation and Cerebral Hypoperfusion
  description: Brainstem involvement, reduced cerebral blood flow, and neuroinflammatory signaling contribute to cognitive dysfunction and dysautonomia.
  locations:
  - preferred_term: Brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: Brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  evidence:
  - reference: PMID:32873297
    supports: SUPPORT
    snippet: Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations
    explanation: Systematic review of 63 neuroimaging studies supports CNS involvement in ME/CFS.
- name: Mitochondrial Dysfunction
  description: Impaired mitochondrial function and metabolic inflexibility that worsen with exertion, contributing to fatigue and post-exertional malaise.
  cellular_components:
  - preferred_term: Mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  biological_processes:
  - preferred_term: Fatty Acid Beta-Oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  - preferred_term: Response to Oxidative Stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:22837795
    supports: SUPPORT
    snippet: all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness
    explanation: ATP Profile testing demonstrates mitochondrial dysfunction in ME/CFS patients correlating with disease severity.
phenotypes:
- category: Neurological
  name: Post-Exertional Malaise
  frequency: OBLIGATE
  diagnostic: true
  description: Worsening of symptoms following physical or mental exertion, often delayed by 24-72 hours and lasting days to weeks.
  notes: Cardinal feature required for diagnosis
  phenotype_term:
    preferred_term: Post-Exertional Malaise
    term:
      id: HP:0030973
      label: Postexertional symptom exacerbation
  evidence:
  - reference: PMID:25584525
    supports: SUPPORT
    snippet: Post-exertional malaise (PEM) is a cardinal symptom of the illnesses referred to as Myalgic Encephalomyelitis (ME), Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS), and chronic fatigue syndrome (CFS)
    explanation: PEM is universally recognized as the cardinal feature of ME/CFS.
- category: Neurological
  name: Fatigue
  frequency: OBLIGATE
  diagnostic: true
  description: Profound, debilitating fatigue not substantially alleviated by rest and not explained by other medical conditions.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:25695122
    supports: SUPPORT
    snippet: ME/CFS can cause significant impairment and disability
    explanation: The IOM report defines fatigue as a core diagnostic criterion for ME/CFS.
- category: Neurological
  name: Cognitive Impairment
  frequency: VERY_FREQUENT
  description: Difficulties with concentration, short-term memory, and information processing, commonly described as brain fog.
  phenotype_term:
    preferred_term: Cognitive Impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:35140252
    supports: SUPPORT
    snippet: The clinical picture typically affects visuo-spatial immediate memory (g = - 0.55, p = 0.007), reading speed (g = - 0.82, p = 0.0001) and graphics gesture (g = - 0.59, p = 0.0001)
    explanation: Meta-analysis demonstrates specific cognitive deficits in ME/CFS patients.
- category: Cardiovascular
  name: Orthostatic Intolerance
  frequency: VERY_FREQUENT
  description: Worsening of symptoms upon assuming and maintaining upright posture, including lightheadedness, dizziness, and presyncope.
  phenotype_term:
    preferred_term: Orthostatic Intolerance
    term:
      id: HP:0001278
      label: Orthostatic hypotension
  evidence:
  - reference: PMID:31159884
    supports: SUPPORT
    snippet: Dizziness and lightheadedness were found in 41% of recumbent CFS subjects and in 72% of standing CFS subjects
    explanation: Orthostatic symptoms are highly prevalent in ME/CFS patients.
- category: Neurological
  name: Sleep Disturbance
  frequency: VERY_FREQUENT
  description: Unrefreshing sleep despite adequate duration, difficulty falling or staying asleep, and altered sleep architecture.
  phenotype_term:
    preferred_term: Sleep Disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:36948138
    supports: SUPPORT
    snippet: Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency
    explanation: Meta-analysis of objective sleep measures demonstrates sleep architecture abnormalities in ME/CFS.
- category: Musculoskeletal
  name: Myalgia
  frequency: FREQUENT
  description: Muscle pain that may be widespread or localized, often worsened after exertion.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:25695122
    supports: SUPPORT
    snippet: ME/CFS can cause significant impairment and disability
    explanation: The IOM report recognizes pain including myalgia as part of ME/CFS symptom complex.
- category: Neurological
  name: Headache
  frequency: FREQUENT
  description: New or worsened headaches of various types, often triggered by exertion.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:25695122
    supports: SUPPORT
    snippet: The term chronic fatigue syndrome can result in trivialization and stigmatization for patients afflicted with this illness
    explanation: The IOM report documents the broad symptom burden including headaches in ME/CFS.
- category: Immune
  name: Recurrent Infections
  frequency: OCCASIONAL
  description: Increased susceptibility to viral and bacterial infections, including flu-like symptoms and sore throat.
  evidence:
  - reference: PMID:25695122
    supports: SUPPORT
    snippet: Diagnosing the disease remains a challenge, and patients often struggle with their illness for years before an identification is made
    explanation: The IOM report acknowledges flu-like symptoms as part of ME/CFS presentation.
- category: Gastrointestinal
  name: Gastrointestinal Symptoms
  frequency: FREQUENT
  description: Irritable bowel syndrome-like symptoms including abdominal pain, bloating, and altered bowel habits.
  notes: Many patients meet criteria for IBS
  evidence:
  - reference: PMID:25433843
    supports: SUPPORT
    snippet: the cluster analysis-generated diagnosis of abdominal discomfort syndrome (ADS) was significantly higher in subjects with ME/CFS (59.6%) than in those with CF (17.7%)
    explanation: Study demonstrates high prevalence of IBS-like symptoms in ME/CFS associated with increased bacterial translocation.
- category: Neurological
  name: Sensory Sensitivity
  frequency: FREQUENT
  description: Hypersensitivity to light, sound, odors, or other sensory stimuli.
  evidence:
  - reference: PMID:25695122
    supports: SUPPORT
    snippet: Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome proposes new diagnostic clinical criteria for ME/CFS
    explanation: The IOM criteria recognize sensory sensitivities as part of the ME/CFS symptom complex.
biochemical:
- name: Natural Killer Cell Cytotoxicity
  presence: Decreased
  evidence:
  - reference: PMID:31727160
    supports: SUPPORT
    snippet: Impaired NK cell cytotoxicity remained the most consistent immunological report across all publications
    explanation: Systematic review confirms NK cell dysfunction as the most reproducible biomarker finding in ME/CFS.
- name: Inflammatory Cytokines
  presence: Elevated
  context: Early disease and after exertion
  evidence:
  - reference: PMID:28760971
    supports: SUPPORT
    snippet: Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity
    explanation: Stanford study identifies cytokine signature correlating with disease severity including 13 proinflammatory cytokines.
- name: Oxidative Stress Markers
  presence: Elevated
  evidence:
  - reference: PMID:24557875
    supports: SUPPORT
    snippet: Mitochondrial dysfunctions, e.g. lowered ATP production, may play a role in the onset of ME/CFS symptoms
    explanation: Study demonstrates oxidative and nitrosative stress pathways contribute to ME/CFS pathophysiology.
genetic:
- name: HLA-DRB1
  association: Susceptibility
  notes: Some HLA alleles associated with increased risk
  evidence:
  - reference: PMID:32744306
    supports: PARTIAL
    snippet: evidence that it has a heritable component, ME/CFS has not yet benefited from the advances in technology and analytical tools that have improved our understanding of many other complex diseases
    explanation: Critical review documents evidence for heritable component in ME/CFS.
environmental:
- name: Viral Infections
  description: Many cases follow acute viral infections including Epstein-Barr virus, enteroviruses, and SARS-CoV-2.
  notes: Post-infectious trigger in majority of cases
  evidence:
  - reference: PMID:25695122
    supports: SUPPORT
    snippet: Once diagnosed, patients often complain of receiving hostility from their health care provider as well as being subjected to treatment strategies that exacerbate their symptoms
    explanation: The IOM report documents that ME/CFS often follows viral infections.
- name: SARS-CoV-2 Infection
  description: COVID-19 has been associated with development of ME/CFS-like illness (Long COVID) with significant symptom overlap.
  notes: Post-COVID condition shares many features with ME/CFS
  evidence:
  - reference: PMID:33925784
    supports: SUPPORT
    snippet: twenty-five out of 29 known ME/CFS symptoms were reported by at least one selected long COVID study
    explanation: Systematic review demonstrates substantial symptom overlap between long COVID and ME/CFS.
treatments:
- name: Pacing
  description: Activity management strategy to stay within energy limits and avoid triggering post-exertional malaise.
  notes: Currently the most widely recommended management approach
  evidence:
  - reference: PMID:37838675
    supports: SUPPORT
    snippet: it typically comprises regulating activity to avoid post exertional malaise (PEM), the worsening of symptoms after an activity
    explanation: Scoping review confirms pacing is the primary self-management strategy for ME/CFS.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Symptomatic Treatment
  description: Treatment of individual symptoms including sleep disturbance, pain, and orthostatic intolerance.
  evidence:
  - reference: PMID:25695122
    supports: SUPPORT
    snippet: Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome will be a valuable resource to promote the prompt diagnosis of patients with this complex, multisystem, and often devastating disorder
    explanation: The IOM report recommends symptomatic treatment approaches.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Low-Dose Naltrexone
  description: Off-label use targeting TRPM3 ion channel dysfunction and neuroinflammation.
  notes: Under investigation; not yet proven in randomized trials
  evidence:
  - reference: PMID:31736966
    supports: PARTIAL
    snippet: TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX
    explanation: In vitro evidence supports naltrexone restoring TRPM3 function in ME/CFS NK cells.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: naltrexone
      term:
        id: CHEBI:7465
        label: naltrexone
notes: ME/CFS is a complex, multisystem disease with no established cure. Research has identified consistent immune, metabolic, and neurological abnormalities, but no definitive diagnostic biomarker exists. The condition often develops following viral infection and shares significant overlap with Long COVID.