A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome.

Observed Findings

• Of 2,073 chronic fatigue patients, 1,578 (76.2%) met Fukuda criteria and 951 (60.3% of Fukuda-positive cases) met Holmes criteria.
• Holmes criteria were more strongly associated with higher symptom severity and broader symptom prevalence across multiple domains.
• Fukuda criteria selected less severely affected patients, leading to greater clinical heterogeneity within the diagnosed group.
• Discriminant function analysis identified that symptom severity and prevalence patterns could differentiate CFS from non-CFS chronic fatigue.
• Addition of 10 symptom variables improved the sensitivity, specificity, and accuracy of CFS patient selection.

Inferred Conclusions

• The Holmes criteria define a more homogeneous, severely affected ME/CFS population than the Fukuda criteria.
• Current diagnostic criteria should be refined by incorporating additional symptoms and adjusting severity weighting to reduce clinical heterogeneity.
• Single-criterion definitions may inadequately capture the full ME/CFS phenotype; a combined symptom-severity approach may improve diagnostic accuracy.
• European ME/CFS populations show similar patterns of symptom heterogeneity as reported in other regions, supporting the generalizability of this concern.

Remaining Questions