BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients.RESEARCH QUESTION: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN? STUDY DESIGN AND METHODS: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Restto-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO 2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO 2 tertiles.RESULTS: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 AE 2 vs 8.3 AE 1.5; P < .0001) and peak VO 2 (80% AE 21% vs 101.4% AE 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% AE 19% vs 99.5% AE 23.8% vs 99.9% AE 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low-and normal-flow participants (0.74% AE 0.1% vs 0.88 AE 0.11 vs 0.86 AE 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation #5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures.

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