Research Directions

NoteOpen Question: What Would Resolve the Splitting vs. Lumping Debate?

The following evidence would most directly resolve the nosological questions in this chapter:

  1. Proteome-wide unbiased autoantibody screening (REAP or equivalent) in ME/CFS, Long COVID, fibromyalgia, and PTLDS — identical to the Nemani 2026 protocol in schizophrenia. If each condition shows a distinct autoantibody profile, splitting is supported. If all conditions share the same profile with only quantitative differences, lumping is supported. If all are null (like the Germain 2025 REAP screen in ME/CFS), the autoimmune-autonomic hypothesis is weakened across the entire cluster.

  2. Head-to-head 2-day CPET in matched cohorts of ME/CFS, Long COVID, fibromyalgia (PEM-positive and PEM-negative subgroups), PTLDS, and GWI. This would determine whether CPET-2 deterioration is specific to ME/CFS, shared across the PEM-positive cluster, or absent across all non-ME/CFS conditions.

  3. Longitudinal cohort following patients from index infection (COVID, Lyme, EBV, Q fever) through 5 years. This would answer: what proportion of each post-infectious syndrome converges on ME/CFS? What proportion diverges into a distinct phenotype? What baseline markers predict trajectory?

  4. Local genetic correlation analysis (LAVA or ρ-HESS) for ME/CFS-FM-IBS at glutamatergic, serotonergic, and autonomic loci. This would identify which shared pathways are truly pleiotropic vs which reflect allelic heterogeneity with tissue-specific regulation.

  5. Trial stratifying by PEM status rather than diagnosis for exercise-based, pharmacological, and neuromodulatory interventions. This would test whether the cross-condition PEM dimension is a stronger predictor of treatment response than the diagnostic label.

Consequence: The nosological questions in this chapter are empirically testable — they will be resolved by the experiments listed above, not by further clinical description or expert consensus.