Table 1.

Proposed characterization of disease stages in an individual with ME/CFS, within the framework of natural history of diseases.

Timing	No disease	Onset	0–4 months¶	4–24 months*	2 years +†
Stage	Predisposition	Trigger and pre-illness	Prodromal period	Early disease	Established disease
Clinical phenotype	No symptoms	Non-specific or related to triggering “insult”	Fatigue-complex symptoms‡	Fatigue-complex symptoms‡ variable severity and progress	Mild, moderate, severe and complicated disease
Prevention level¶	Primary prevention	Treatment of “insult” and primary prevention	Secondary prevention	Treatment and secondary prevention	Treatment and tertiary prevention
Recovery Potential§			Likely	Possible	Less likely
Pathophysiology	Predisposing factors	Non-specific host response and related to specific trigger factor	Neuro-immune response to insult and fight for homeostasis	Neuro-inflammation and systemic consequences; aberrant homeostasis	Systemic disease, aberrant or failed homeostasis

^*3–6 months is commonly proposed as the minimum period of symptoms before diagnosis is made in children and adults, respectively (32).

2 years has been used as a cut off to distinguish between short and long term duration of disease (94, 95), but its use as defining established disease is variable and depends on a range of factors, including individual response to early disease.

^‡Fatigue-complex symptoms: initially predominantly neuro-immune (prior to early disease), and variable systemic symptoms in established disease.

^§Tentative proportions for recovery are: likely (>75%); possible (<20%); less likely (<5%). “Likely” and “possible” are based on recovery from arboviruses and EBV [(96); 100]; “less likely” is based on reviews on prognosis (97).

^¶The Prevention level will be considered further in a subsequent publication which is being prepared by the authors.