ME/CFS Research Roundup: Brief highlights of biomedical research to date
DISABILITY & QUALITY OF LIFE
People with ME/CFS score lower on measures of physical function and overall quality of life than most other chronic disease groups, including MS, cancer and stroke, and the experience of patients with severe ME/CFS is comparable to end stage HIV or heart failure (Nacul 2011, Falik Hvidberg 2015).
Observed modifications in the status of cellular metabolism genes (deVega 2017, Billing-Ross 2016) and analysis of metabolites and proteins in the blood have shown marked abnormalities in metabolic pathways (Germain 2017, Naviaux 2016, Armstrong 2012), demonstrating that basic energy production mechanisms are dysfunctional and, thus, ME/CFS patients exist in a persistent state of energetic conservation at the cellular level.
A more extensive exploration of this phenomenon specifically identified impaired function of a protein called pyruvate dehydrogenase, a critical enzyme in the pathway that generates ATP, the body’s energy currency (Fluge 2016). For every 38 ATP molecules generated via aerobic metabolism in a healthy person, only 2 ATP are produced by a ME/CFS’s patient’s mitochondria via anaerobic processes, meaning their energy budget for all survival functions is drastically reduced, consistent with patients’ reported experience of profound and unrelenting fatigue.
Collectively, these studies demonstrate that the quantity of physical energy available for cellular functions is severely restricted in ME/CFS patients and their cells are forced to convert to a less efficient mode of energy production, though the root cause of this impairment has not been identified (Morris 2014).
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The hallmark feature defining ME/CFS is the experience of worsening of all symptoms [fatigue, feeling “unwell” (malaise), cognitive impairment, sensory hypersensitivity, pain, etc.] following physical or cognitive exertion, often at extremely minimal thresholds of activity (VanNess 2010). This is known as post-exertional malaise (PEM) and distinguishes ME/CFS from confounding disorders, such as depression, where patients conversely feel better after exertion. Carefully constructed studies of ME/CFS patients’ physiologic response to exertion at several time intervals have revealed objective biologic measures of oxygen utilization which pinpoint the metabolic switch from aerobic to anaerobic metabolism (Snell 2013, Keller 2014), corroborating patients’ reported PEM symptoms and other researchers’ findings of metabolic dysfunction.
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A sizable and longstanding body of evidence from imaging studies demonstrates abnormalities in the central nervous systems of ME/CFS patients. Several brain MRI analyses have shown reduced white and gray matter volumes indicating long-term damage to neurologic tissues, a finding which is consistent with the poor memory and cognitive impairment experienced by patients (Finkelmeyer 2017, Shan 2016, Barnden 2011, Zeineh 2015, Puri 2012, Lange 1999).
More specifically, PET scans of ME/CFS patient brains showed evidence of neuroinflammation indicated by an elevated presence of activated microglial cells, and these levels correlated with the severity of cognitive impairment and pain (Nakatomi 2014). This finding is consistent with reports that some glial cell inhibitors can improve patients’ condition (Younger 2014).
The vagus nerve, which travels from the brainstem through the abdomen and interfaces with many major organ systems, delivers the “rest and digest” signal from the parasympathetic nervous system as an antidote to the activated “fight or flight” state induced by the sympathetic nervous system. Dysfunction in these processes is thought to be at the root of symptoms such as heart rate variability, sleep disturbance and orthostatic intolerance experienced in ME/CFS (Morris 2013), and this has been recently postulated to be caused by impaired function of the vagus nerve, possibly due to direct vagal nerve infection (VanElzakker 2013).
Numerous examinations of markers of inflammation, called cytokines, in the blood of ME/CFS patients have yielded mixed results, confounding researchers for years. However, several investigations have demonstrated marked elevations in classical inflammatory cytokines in the blood, indicating systemic inflammation (Mildrad 2017, Maes 2012, deVega 2014, Smylie 2013, Brenu 2011), as well as in the cerebrospinal fluid, indicating neurologic inflammation (Hornig 2016). Recently, clear differences in cytokine levels were identified when subgroups of ME/CFS patients were stratified by typical/atypical patterns or by the duration of their illness, with those ill under 3 years displaying elevated levels and those ill beyond 3 years showing decreased levels relative to controls, possibly explaining prior inconsistent results across various patient cohorts and indicating an intrinsic chronicity in disease progression (Hornig 2015, Landi 2016, Hornig 2017).
Additionally, studies have identified distinct correlations between several cytokines and disease severity, indicating that these factors are likely directly contributing to patients’ symptoms (Montoya 2017, White 2010). Consistent with this, recent preliminary findings identified a subgroup of ME/CFS patients whose blood levels of C-reactive protein (CRP), a hallmark indicator of infection, exactly parallels their reported fatigue over time, indicating that an underlying infection may be responsible for their symptoms (Younger, unpublished, https://youtu.be/QHIvcw9SNFo). Similarly, evidence for the causal element in metabolic dysfunction being a large, soluble factor circulating in the blood serum was provided by a study reproducing ME/CFS metabolic defects in healthy control cells following exposure to ME/CFS patient serum (R. Davis, unpublished, https://youtu.be/vZQgJP47kA4).
Collectively, these findings have conclusively shown ME/CFS to be an inflammatory disease, however the underlying factors driving inflammation remain unidentified and may be varied across subsets of patients with the broad diagnosis of ME/CFS.
Genetic or acquired immunodeficiencies resulting in poor control over pathogens could indicate an underlying cause of illness and serve as useful diagnostic biomarkers in ME/CFS patient screening. Such a deficiency was recently identified in ME/CFS patients displaying reduced levels of a protein essential for natural killer (NK) cell function, an immune cell vital in controlling viral infections (Ngyuen 2017), providing a possible explanation for numerous prior observations of impaired NK cell activity in ME/CFS (Klimas 1990, Maher 2005, Brenu 2011, Brenu 2012, Hardcastle 2015, Huth 2016).
Markedly elevated levels of antibodies to common herpes viruses are often identified in ME/CFS patients, indicating poor control over a pathogen that is generally kept in check by the immune system (Halpin 2017). While it is not known if this phenomenon is a cause or effect of ME/CFS, some patients achieve improvement or full recovery with antiviral medications (Kogelnik 2006, Montoya 2013), suggesting active infection due to immunologic insufficiency.
Analysis of cytokines in ME/CFS has also revealed skewing in the type of inflammation present toward a profile with less potent control over viral infection (called Th2), though the reasons for this alteration are not known (Broderick 2010).
Features of ME/CFS such as female bias, systemic inflammation and a relapsing/remitting pattern parallel those of autoimmune diseases such as multiple sclerosis, lupus or rheumatoid arthritis. Thus it has long been hypothesized that autoimmunity is at play in ME/CFS and a growing body of very recent evidence supports this hypothesis. Depletion of B cells (which produce antibodies) from ME/CFS patients’ blood using a drug called Rituximab (a successful therapy in other autoimmune diseases) has recently shown dramatic improvements in some patients (Fluge 2011, Fluge 2015).
Antibodies targeting two proteins on the surface of neural and muscle tissues, beta-adrenergic and muscarinic acetylcholine receptors were identified in a high proportion of ME/CFS patients by multiple independent research groups (Loebel 2016, Light and Bergquist, unpublished, https://youtu.be/xDQL7v4XlRU, https://youtu.be/Zsv5nbpliW8 ).
Additionally, bias in the diversity of targets identified by T cells was recently found in ME/CFS patients at levels comparable to the skewing observed in multiple sclerosis and cancer patients’ T cells, indicating that the immune system is continually activated to fight a particular target (M Davis, unpublished, https://youtu.be/SbnCMOHOL28).
Such findings have strengthened the belief among many researchers that autoimmunity is at the root of ME/CFS symptomatology, even if triggered by an initial infection (possibly via a process called molecular mimicry) or facilitated by a chronic state of inflammation initiated by an infectious pathogen (Morris 2014).
A number of profiling studies have shown in ME/CFS alterations to the diversity of bacteria, viruses and parasites that populate the intestinal tract, termed the “gut microbiome” (Giloteaux 2016, Nagy-Szakal 2017, Fremont 2013, Shukla 2015, Giloteaux 2016). However, whether this phenomenon is a cause of disease, a contributor to symptoms, or a product of altered inflammatory states in ME/CFS remains to be determined.