Background: The pathophysiology underlying exertional intolerance in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains poorly understood. Previously, a single-dose of 60 mg pyridostigmine, a reversible acetylcholinesterase inhibitor, was found to acutely improve aerobic capacity (Joseph, P. et al. Chest 2022; 162:1116?26).

Aims: To build upon these prior findings, this study aimed to evaluate the long-term effect (>1 month) of pyridostigmine treatment on exercise intolerance in ME/CFS. 

Methods: Between 2017-2022, patients who met the National Academy of Medicine criteria for ME/CFS, and had a minimum of two clinical, constant load, submaximal exercise tests (Shape Medical System, MN) were evaluated. Patients who began pyridostigmine after their baseline test were considered the treatment group. Measurements were taken at baseline (T₀) and most recent follow-up (T₁). 

Results: At the follow-up evaluation (690 ± 547 days), the treatment group (n=37, dose range: 24-360mg/d) demonstrated a significant increase in oxygen uptake efficiency slope (OUES) (T₀: 1.82 ± 0.56, T₁: 1.98 ± 0.53; p=0.044) and pulmonary vascular capacitance (PVCAP) (T₀: 486.19 ± 169.89 ml*mmHg, T₁: 540.03 ± 170.59 ml*mmHg; p=0.040). These differences were not observed in the control group (n=16) OUES (T₀: 1.62 ± 0.40, T₁: 1.77 ± 0.47; p=0.268) and PVCAP (T₀: 446.94 ± 144.80 ml*mmHg, T₁: 465.81 ± 124.34 ml*mmHg; p=0.590).

Conclusion: Long-term treatment with pyridostigmine improved aerobic capacity in ME/CFS as demonstrated by an increase in OUES, mediated by improvements in central hemodynamics (PVCAP).