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How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) progresses. The natural history of ME/CFS
We propose a framework for understanding and interpreting the pathophysiology
of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that considers
wider determinants of health and long-term temporal variation in pathophysiological
features and disease phenotype throughout the natural history of the disease. As in
other chronic diseases, ME/CFS evolves through different stages, from asymptomatic
predisposition, progressing to a prodromal stage, and then to symptomatic disease.
Disease incidence depends on genetic makeup and environment factors, the exposure
to singular or repeated insults, and the nature of the host response. In people
who develop ME/CFS, normal homeostatic processes in response to adverse insults
may be replaced by aberrant responses leading to dysfunctional states. Thus, the
predominantly neuro-immune manifestations, underlined by a hyper-metabolic state,
that characterize early disease, may be followed by various processes leading to
multi-systemic abnormalities and related symptoms. This abnormal state and the effects
of a range of mediators such as products of oxidative and nitrosamine stress, may
lead to progressive cell and metabolic dysfunction culminating in a hypometabolic
state with low energy production. These processes do not seem to happen uniformly;
although a spiraling of progressive inter-related and self-sustaining abnormalities may
ensue, reversion to states of milder abnormalities is possible if the host is able to
restate responses to improve homeostatic equilibrium. With time variation in disease
presentation, no single ME/CFS case description, set of diagnostic criteria, or molecular
feature is currently representative of all patients at different disease stages. While
acknowledging its limitations due to the incomplete research evidence, we suggest the
proposed framework may support future research design and health care interventions
for people with ME/CFS