Myalgic encephalomyelitis/chronic fatigue syndrome [CFS] is a disabling illness primarily affecting women. Post exertional malaise [PEM], thought to be the sine qua non of CFS, takes the form of a broad increase in symptoms occurring sometime after the cessation of often minimal exertion. Capturing and quantifying PEM remains problematic. Recent reports pointing to a possible metabolic deficit occurring on the second of two sequential cardiopulmonary exercise tests [CPET] done to exhaustion have attracted a great deal of attention for two reasons: as a metabolic manifestation of PEM and for use in proving patient disability. Specifically, the initial reports indicated that CFS patients failed to replicate their metabolic peak VO2 result on the second day of testing with an earlier onset of the anaerobic threshold defined as the oxygen consumption at the ventilatory threshold (VO2VT). Subsequent studies did not confirm the inability to replicate the peak VO2 on day #2 but did confirm the reduction in VO2VT from levels seen on day #1. However, we identified two problems with the work that has been done on 2-CPET testing: (1) the results are always presented as aggregate differences from day #1 to day #2 across different patients. Since CFS is defined clinically, it probably is comprised of multiple subgroups all with the same phenomenology but different pathophysiological causes. This would mean that only some – but not every – patient would show the abnormality in VO2VT on day #2 or severe PEM thereafter. (2) Although the researchers claim that this abnormality is a marker of PEM, there are no data linking patients who show this cardiopulmonary abnormality to the timing and severity of PEM. The overarching goal of this proposal is to overcome these deficiencies. A critical still unanswered question is why some CFS patients manifest VO2VT earlier on day #2 of CPET. We hypothesize that the reason for this is due to reduced total blood volume [TBV] leading to a reduced stroke volume [SV]. One of our early studies showed reduced SV in a subgroup of severely ill patients; later work from another group confirmed this finding, also in severely ill patients, and provided evidence to attribute this to reduced TBV. We hypothesize that exercise on day #1 will lead to insensible fluid loss related to sweating and deep rapid breathing which will further exacerbate thatthese changes will lead to decreases in reductions in TBV and SV. Accordingly, we hypothesize VO 2VTon day #2 CPET and that these decreases may be prevented by fluid expansion. We will evaluate these hypotheses by stratifying CFS on severity of symptoms, by determining TBV before each CPET, by measuring stroke volume during exercise using an inert gas rebreathing method, and by replenishing circulating volume intravenously for half the subjects shown to have reduced blood volume before day #2 testing. Finally we will determine how these changes relate to PEM. We will study 80 CFS patients [40 in the Severe and 40 in the Non-Severe categories] and compare the data from them to 40 matched healthy controls to address four aims to answer these research questions.

PROJECT NARRATIVE We plan to determine why post-exertional malaise occurs, to which patients and at what level of severity. The changes in cardiopulmonary physiology reported to occur on the second of two sequential days of maximal exercise testing have been reported to be a physiological manifestation of PEM. This proposal seeks to use this two day exercise protocol to understand the physiology of PEM and how it is linked to its behavioral manifestations of reduced activity and markedly increased symptoms.