150 ME/CFS patients who had been seen at Bateman Horne Center (Salt Lake City, UT) for routine clinical care between February 2018 and September 2019 and 75 matched HCs were recruited for the study. The 150 MECFS subjects included 75 sick with ME/CFS for < 4 years (< 4 ME/CFS) and 75 sick for greater than 10 years (> 10 ME/CFS). The age range of ME/CFS participants and HCs was 18–65 years at the time of informed consent. HCs were matched with < 4 ME/CFS participants by age (± 5 years), gender and ethnicity. Enrolled ME/CFS participants were required to fulfill the International Chronic Fatigue Syndrome Study Group research criteria , the Canadian Consensus Criteria , and the IOM clinical diagnostic criteria . HCs were recruited from the Salt Lake City metropolitan area using advertisements posted on social media, the clinic webpage or by phone contact with a volunteer pool from previous studies. HCs were considered generally healthy and between 18 and 65 years of age. HCs were excluded if they fulfilled ME/CFS diagnostic criteria or had a history of illness, had a BMI > 40 or had been treated with long-term (longer than 2 weeks) antiviral medication or immune modulatory medications within the past 6 months or had been treated with short-term (less than 2 weeks) antiviral or antibiotic medication within the past 30 days.
Baseline (Year 1) assessments
All research participants had a physical examination at the baseline visit in Year 1 that included evaluation of vital signs, body mass index (BMI), orthostatic vital signs, skin, lymphatic system, HEENT, pulmonary, cardiac, abdomen, musculoskeletal, nervous system and fibromyalgia (FM) tender points. Medical history and concomitant medications were documented. The 10-minute NLT was conducted following the physical examination. The 10-minute NLT is an orthostatic challenge standing lean test. It requires an exam table, a pulse oximeter placed on one hand and a blood pressure cuff placed on the opposite arm. Objective hemodynamic parameters (i.e. HR and BP) were recorded while subjects were resting supine for 10 min, then moved to a standing position and remained standing for 10 min. Testing requires at least one person to scribe and monitor HR, signs, and symptoms and one person to obtain BP measurements. Participants were first asked to lie down undisturbed for 10 min. The participant was then asked to stand and lean against a wall with only shoulder blades touching and heels 6–8 inches from the wall. BP and HR are recorded every minute for 10 min and participants were asked to report any symptoms they experienced.
In addition, all subjects completed the following questionnaires before their baseline visit using REDCap, a secure and HIPAA compliant electronic data capture system; DePaul Symptom Questionnaire, Post-Exertional Fatigue Questionnaire, RAND-36, Fibromyalgia Impact Questionnaire-R, ACR 2010 Fibromyalgia Criteria Symptom Questionnaire, Pittsburgh Sleep Quality Index, Stanford Brief Activity Survey, Orthostatic Intolerance Daily Activity Scale, Orthostatic Intolerance Symptom Assessment, Brief Wellness Survey, Hours of Upright Activity, medical history and family history.
Systolic BP (SBP), diastolic BP (DBP) and HR were used as raw values recorded during the 10-minute NLT. Pulse pressure (PP) and narrowed pulse pressure (NPP) were calculated according to the consensus equation: PP = SBP- DBP and NPP = PP/SBP. PP is considered abnormally narrow if it is less than 25% of SBP . Subgroup analysis of < 4 and > 10 ME/CFS participants was conducted. For assessing OI manifestations, changes in HR and BP during the 10-minute NLT were classified as follows. OH was defined as a decrease in SBP of 20 mm Hg or more, or a decrease in DBP of 10 mm Hg or more in the first 3 min standing compared to resting supine values. POTS was defined as an increase of HR greater than 30 bpm or a HR of greater than 120 bpm, based on the average of the last three minutes standing. (e.g., if the standing portion of the test was terminated at 6 min, we calculated the mean of the data recorded during the 3rd, 4th and 5th minutes). This allowed us to include results from participants unable to complete the 10-minute NLT. OI symptoms were spontaneously reported by participants during the test. OI signs were observed and recorded by the scribe. We conceptualized OI symptoms by identifying and refining common words or concepts mentioned by participants. To assess the relationship between self-reported hours of upright activity (HUA) and hemodynamic changes during the 10-minute NLT, multiple linear regression was performed between the average values of hemodynamics data: SBP, DBP, HR, PP, and NPP in last 3 min standing. Also, additional multiple logistic regression was performed for comparing hemodynamics between ME/CFS patients with < 5 HUA and > 5 HUA. HUA is defined as time spent with feet on the floor (sitting, standing, walking) in the last 24 h.
Data were analyzed by Excel and STATA/MP 13.1 Windows [32-bit] version. All demographic data of subgroups were compared using ANOVA or T-test, where appropriate. Repeated measures of ANOVA were used to detect differences in hemodynamic data of each subgroup in each minute and presented as Means (SD). Fisher’s Exact test was applied to demonstrate association between comprehensive hemodynamics trend results in each subgroup. Descriptive statistics used for spontaneous OI symptom reports. The relationship between the hemodynamic response and HUA was modeled by multiple linear regression after adjusting for age and gender. Effect modification by medication was evaluated via stratified analyses and tested via the interaction term approach. Logistic regression was used to analyze HUA. T-test, F-test and Chi-Square test were used for validating models. A p-value of < 0.05 was considered statistically significant.