Sex Differences in Exercise-related Post-exertional Malaise in ME/CFS
Conditions: Chronic Fatigue Syndrome
Sponsor: Stony Brook University

 
 
 
Protocol  
for Submissions to CORIHS 
 
TITLE:  Sex differences in exercise-related post-exertional malaise in ME/CFS 
 
INVESTIGATORS:   Fred Friedberg, Jenna Adamowicz, Shannon Fitzgerald, Patricia Bruckenthal, Jie Yang. 
 
    
A. SPECIFIC AIMS 
Specific Aim 1: After two high-effort six minute walk tests conducted on consecutive days, female subjects with 
ME/CFS as compared to male ME/CFS subjects will show slower recovery to resting baseline with respect to 
cardiac autonomic functioning (HRV, BP), physical functioning, and symptom resolution.  
 
Specific Aim 2: Female subjects with ME/CFS as compared to males with ME/CFS will show greater adverse 
impact on autonomic and physical functioning and symptom severity after the day 2 exercise test. 
 
 
B. BACKGROUND AND SIGNIFICANCE  
Post-exertional malaise (PEM), i.e., prolonged symptom flare-ups lasting at least 24 hours after 
physical activity, is a debilitating symptom of chronic fatigue syndrome (CFS) experienced by many but 
not all patients.  PEM appears to negatively impact both physical and cognitive abilities. 
 
In the literature, patient reactions associated with PEM have included increased symptoms of pain and 
fatigue, [1–3] abnormal cardiopulmonary responses to exercise, [4, 5] decreases in physical activity 
behaviors, [2, 6, 7] changes in cognitive function [8, 9] and up-regulation of numerous biological 
variables. [10, 11] Although a number of studies have been conducted, consistent results and/or 
replication of findings have been rare. [12] 
  
                 In addition, sex differences in heart rate variability (HRV) and blood pressure (BP), the key 
autonomic variables in this study, are more likely to be identified during exercise recovery (19, 20). These 
studies found slower exercise recovery in women with respect to both HRV and BP.  Regarding ME/CFS 
patients, sex differences have been recently reported with respect to greater symptom severity and lower 
functioning in women vs. men (21) which may indicate a greater susceptibility to prolonged symptom flare-ups 
in women, as reflected in PEM (19). Thus, we hypothesize that the repeat exercise test protocol is more likely 
to reveal sex differences indicating higher PEM severity, greater autonomic imbalance, and slower recovery 
times in women as compared to men with ME/CFS. 
 
 
 
C.  PRELIMINARY STUDIES 
     Preliminary data (N=73) from the PI’s laboratory indicated that self-report PEM scores at resting baseline 
(frequency x severity ratings of PEM) were positively correlated (p<.05) with fatigue ratings taken immediately 
after and 10 minutes after completion of a standard low exertion 6MWT. This indicates that participants’ PEM 
scores at baseline are predictive of higher fatigue ratings following even a modestly effortful physical exertion 
task (in contrast to the high effort 6MWT proposed). In addition, fatigue scores at baseline increased at both 
10- (p=.013) and 20-minutes (p=.005) after completion of the walk test. By comparison, in healthy subjects, the 
six minute walk test is associated with lower post-walk fatigue (18). Thus this preliminary data suggest that the 
abnormal symptom exacerbation characteristic of PEM can be provoked and confirmed by patients after a brief 
exercise task as proposed in this application.   
     In order to ensure PEM provocation, we are scheduling two high effort 6MWTs on consecutive days 
modeled after a recent protocol for 2 day maximal exercise testing in ME/CFS (8, 9). The study-scheduled day 
two test is intended to take advantage of the prolonged nature of PEM (1, 2) which lasts 24 hours or more 
(subjects will be screened for this symptom). Thus rather than recovering from the day 1 test by day 2, as 
would be the case with healthy individuals, PEM for the ME/CFS participants is expected to be even greater on 
day 2, providing another opportunity to assess exercise recovery abnormalities. Of particular interest is the 

 
 
 
trajectory of potential sex differences during the post-exercise recovery period and its implications for 
biomarkers of illness status with possible implications for activity management.  
  
 
D. RESEARCH DESIGN AND METHODS 
  
1. Rationale/overview 
The rationale for the proposed study is to identify abnormalities provoked by repeated knee 
squats (30 sec.) and six minute walk tests in individuals with CFS who report the symptom of 
post-exertional malaise.  
 
2. Research Site 
SBUH: Psychiatry department in the HSC. 
 
3. Study sample 
The study sample will consist of males and females with ME/CFS who report significant post-
exertional malaise.  We will conservatively assume a pre-enrollment withdrawal rate of 20% and 
an assumed 20% post-enrollment attrition rate. In order to achieve an endpoint sample of 32, 
the initial sample will be 40 (phone-screened) enrolled participants. About 5  new patients a 
month will be needed over the 8-month recruitment period to yield a baseline sample of 40 
ME/CFS patients. Study ads will emphasize that the study will help to advance our 
understanding of ME/CFS.  
 
4. Screening 
Inclusion criteria: These are: patients aged 18-65 of both sexes who are considered physically capable of doing 
the exercise tasks and are willing to wear a heart monitor (10 min/day) and an actigraph (16 days; waking hours 
only). Subjects must also meet our validated phone-screen eligibility for ME/ CFS criteria (38; Appendix 1)) which 
will require the symptom of PEM. To assess patient-reported PEM during the phone screen, a PEM score will 
be obtained (frequency x severity of the symptom of PEM; pilot study (above). Only those subjects with self-
reported persistent presence of moderate to high intensity PEM lasting at least 24 hours will be study-eligible 
(>75% of ME/CFS subjects report long duration PEM; 2, 6).  In addition, 3 out of 7 secondary symptoms of 
ME/CFS are required (apart from PEM), i.e., headaches, tender lymph nodes, sore throat, myalgias, arthralgias, 
sleep disturbance, and/or problems with memory or concentration. A physician note confirming a CFS diagnosis 
will be requested. 
Medical exclusions as determined by the validated phone screen interview (14), will consist of cases of fatigue 
clearly attributable to self-report medical conditions such as untreated hypothyroidism, unstable diabetes 
mellitus, organ failure, chronic infections, and chronic inflammatory diseases, or AIDS.  Exclusionary 
psychiatric disorders include any psychosis, or alcohol/ substance abuse within two years prior to illness onset 
and any time afterward, and current or past depression with melancholic or psychotic features within 5 years 
prior to onset of ME/CFS or anytime afterward (14). Self-report pregnancy is also an exclusion. Two other 
exclusionary criteria will be used: a) patients on heart medication or patients not dose-stabilized for at least 3 
months on antidepressant drugs; b) patients at significant risk of suicide or in need of urgent psychiatric 
treatment. As much as possible, appropriate medical and psychiatric referrals to facilities local to subjects will 
be provided.  
 
The structured screening phone interview was shown to be 98% reliable in the PI's previous study [14] in 
screening out exclusionary medical and psychiatric disorders in chronic fatigue evaluation when compared to 
subsequent study-based medical evaluations and clinical interviews using the Structured Clinical Interview for 
DSM-IV. 
 
5. Procedures 
To initially verify patient-reported post-exertional malaise (PEM) (or its absence), subjects will be asked several 
questions about their symptoms of  PEM (frequency, duration, intensity) during the phone screen and a PEM 
score will be obtained (based on previous pilot data). Subjects with self-reported presence (lasting at least 24 

 
 
 
hrs.) will be assigned to a physically exerting task.  These repeat exertion tasks will ensure that PEM is 
triggered, a critical aspect of the study.   
The physically exerting task will consist of the following: 30 sec. of knee squats followed by two six minute walk 
tests to generate PEM. Heart rate and blood pressure will be measured during these tests. These repeat 
exertion tasks will ensure that PEM is triggered, a critical aspect of the study. During the baseline week and the 
followup week, subjects will wear actigraphs (daytime hours) and heart monitors (10 min/day) and record their 
symptoms in an online diary. 27 females and 13 males will be initially enrolled.  
 
 
Payment to Subjects 
 
The total compensation to be paid for each participant will be up to $100.Participants will be paid in 
installments as they complete each aspect of the study (baseline, exercise tests, follow-up) Participants will be 
paid $50 for completion of the one-week baseline assessment (two six minute walking tests, questionnaires, 
activity and heart monitors). For the one-week follow-up, participants will be paid an additional $50 for 
completion of the activity and heart monitors. 
 
E.  STATISTICS 
Data analysis will be done with independent and paired t-tests, chi square, ANOVA, and Pearson correlations.  
 
 
F. FUNDING STATUS, DETAILS 
This study is fully funded by NIH. 
 
 
G.  HUMAN SUBJECTS RESEARCH PROTECTION FROM RISK 
 
Risk to Subjects 
 
 
Documentation of all study activities will be reviewed by the study staff to ensure the protocol is adhered to. 
Any significant adverse events will be documented and immediately reported to the PI.  
 
 
Potential Benefits of Proposed Research to the Subjects and Others 
There is no health benefit to subjects.  
 
Importance of the Knowledge to be Gained 
Participation will advance the understanding of chronic fatigue syndrome.  
 
H.   DATA SAFETY MONITORING PLAN (for more than minimal risk studies)  
 
This study is minimal risk. 
 
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