ME/CFS: Phenotypic Overlap with Infection-Associated Syndromes and Craniofacial Sampling for Neuroimmune Investigation
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) affects up to 3.3 million Americans, yet its pathogenesis remains poorly understood. To support ME/CFS research, we developed two targeted evidence syntheses: (i) phenotypic overlap between ME/CFS and syndromes associated with SARS-CoV-2, Epstein-Barr virus (EBV), and other pathogens; and (ii) needle-free, incision-free craniofacial sampling sites anatomically linked to intracranial sites with pathogen detection. To illustrate pathogen detection constraints, we examined EBV studies in ME/CFS conducted by U.S.-affiliated investigators. Only 1 of 21 studies (4.8%) measured EBV nucleic acids or viral proteins, and sampling was restricted to capillary blood. These design limitations may reduce sensitivity to intracranial infection or inflammation, including processes involving EBV, a virus implicated in multiple sclerosis and an encephalitis variant with overlapping clinical features. Observed challenges motivated the proposal of two reporting frameworks, J.O.A.N. and M.I.K.E.: J.O.A.N. aims to reduce false-negative risk in pathogen detection studies while M.I.K.E. seeks to advance neuroimmune research with needle-free, incision-free craniofacial sampling. Overall, the current understanding of ME/CFS may be incomplete due to methodological gaps. If ME/CFS, like Long COVID, encompasses biologically distinct subgroups, these syntheses and frameworks could support more rigorous investigation and interpretation.
