Myalgic Encephalomyelitis Chronic Fatigue at the National Institutes of Health

Objective:

The primary objective is to explore the clinical and biological phenotypes of post-infectious
myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS). The secondary objective is to
explore the pathophysiology of fatigue and post-exertional malaise (PEM).

Study population:

Up to 206 persons will be enrolled as part of this protocol. Up to 150 persons aged 18-60
will be part of 3 study groups: 50 ME/CFS patients whose fatigue began after an infection, 50
non-fatigued participants with a documented history of Lyme disease exposure and treatment,
and 50 healthy volunteers. The study has a target of completing all study procedures on 20
enrolled participants in each group. Up to an additional 36 persons reporting a community
diagnosis of ME/CFS will be enrolled into focus groups to discuss the experience of
post-exertional malaise. Up to an additional 10 healthy volunteers and 10 ME/CFS patients may
be enrolled to refine the protocol's electrophysiological and neuroimaging techniques.

Design:

This is a single-center, exploratory, cross-sectional study of PI-ME/CFS. Participants will
have a phenotyping visit, which will encompass a 2-5 day long inpatient admission at the NIH
Clinical Center. Case status for ME/CFS participants will be determined after the phenotyping
visit by a case adjudication process utilizing an expert physician committee and published
guidelines. Adjudicated participants meeting inclusion criteria will be invited back to
participate in an exercise stress visit, which will encompass a 5-10 day long inpatient
admission. Detailed subjective and objective measurements and biological specimens will be
serially collected before and up to 96 hours after a peak exercise test capable of inducing
post-exertional malaise during this visit. All procedures will be completed on all three
study groups to allow for optimal inter-group comparisons.

Outcome measures:

1. Characterization of the immune system and inflammatory signaling in blood and
cerebrospinal fluid (CSF)

2. Characterization of the pattern of microbiome in gut, blood and CSF

3. Characterization of physical and cognitive fatigue using functional magnetic resonance
imaging and transcranial magnetic stimulation

4. Effect of maximal exertion on neurocognition

5. Effect of maximal exertion on brain function and connectivity

6. Effect of maximal exertion on markers of immune dysfunction and inflammation

7. Effect of maximal exertion on metabolic function

8. Effect of maximal exertion on autonomic function

9. Effect of maximal exertion on gene expression profiles in blood and CSF

- INCLUSION CRITERIA:

- Inclusion criteria for all participants

1. Adult participants aged 18-60 years at the time of enrollment.

2. Self-reported completion of at least the 7th grade of school.

3. Ability to speak, read, and understand English.

4. Willing and able to complete all study procedures

5. Participant has a primary care physician at the time of enrollment.

6. Able to provide informed consent.

- Additional inclusion criteria for participants with PI-ME/CFS for the phenotyping
visit

1. A self-reported illness narrative of the development of persistent fatigue and
post-exertional malaise as the consequence of an acute infection. The persistent
fatigue may have an acute onset or become progressively worse over 6 months.

2. Licensed Independent Practitioner documentation of ME/CFS onset:

- Medical documentation of absence of symptoms within one year of ME/CFS
onset.

- Documentation of a medical evaluation for symptoms of an acute infection or
documentation of a medical evaluation of persistent symptoms within 2 months
following an assumed infection.

3. Persistent fatigue and PEM onset less than 5 years prior to enrollment.

- Additional inclusion criteria for participants with PI-ME/CFS for the exercise stress
visit

1. Be unanimously considered to be a case of PI-ME/CFS by the protocol s
adjudication committee.

2. Meet the 1994 Fukuda Criteria or the 2003 Canadian Consensus Criteria for Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome or the Institute of Medicine
Diagnostic Criteria..

3. Have moderate to severe clinical symptom severity:

- Severe fatigue as determined using the Multidimensional Fatigue Inventory
(MFI): score of greater than or equal to 13 on the general fatigue subscale
or greater than or equal to 10 on the reduced activity subscale.

- Functional impairment as determined using the Short-Form 36 (SF-36): score
of less than or equal to 70 physical function subscale, or less than or
equal to 50 on role physical subscale, or less than or equal to 75 on social
function subscale

- Additional inclusion criteria for healthy volunteer group

- Additional inclusion criteria for Documented Lyme Infection - Asymptomatic group

1. Medical record documentation of fulfilling the probable or confirmed 2017 CDC
Lyme Disease National Surveillance Case Definitions
(https://wwwn.cdc.gov/nndss/conditions/lyme-disease/case-definition/2017/):
Probable: Any other case of physician-diagnosed Lyme disease that has laboratory
evidence of infection.

- Confirmed:

- A case of EM with exposure in a high incidence state (as defined
above), OR

- A case of EM with laboratory evidence of infection and a known exposure
in a low incidence state, OR

- Any case with at least one late manifestation that has laboratory
evidence of infection.

- Laboratory Evidence:

- A positive culture for B. burgdorferi, OR

- A positive two-tier test. (This is defined as a positive or equivocal
enzyme immunoassay (EIA) or immunofluorescent assay (IFA) followed by a
positive Immunoglobulin M1 (IgM) or Immunoglobulin G 2 (IgG) western
immunoblot (WB) for Lyme disease) OR

- A positive single-tier IgG2 WB test for Lyme disease3..

EXCLUSION CRITERIA:

- Exclusion criteria for all participants

1. Current or past psychotic disorder including depression with psychosis, bipolar
disorder, and schizophrenia

2. Current DSM-5-defined major depression disorder, generalized anxiety disorder,
post-traumatic stress disorder, panic disorder, or obsessive-compulsive disorder
unless managed for more than six months with a stable treatment regimen

3. Current or prior substance use disorder as diagnosed on the Structured Clinical
Interview for DSM-5 (SCID-5) or positive urine toxicology results at enrollment

4. Current suicidal ideation

5. History of head injury with loss of consciousness or amnesia lasting greater than
a few seconds within lasta five years or lasting greater than 5 minutes at any
point during their lifetime.

6. Women who are pregnant, actively seeking to become pregnant, or have been
pregnant in the year prior to study enrollment.

7. Current or previous malignancy. Certain dermatologic malignancies (e.g. basal
cell carcinoma) will be allowed. A history of malignancy that have fully resolved
with surgical resection only (i.e. no chemotherapy, radiation therapy, or
immunotherapy) will be allowed.

8. Current immunologic disorder (e.g. Type 1 diabetes, rheumatoid arthritis) will be
assessed on a case-by-case basis. Allergies requiring anti-histamines may not be
an exclusion, but allergies requiring immunosuppressants may be an exclusion.

9. Current or previous long term immune suppressive or immunomodulatory therapy.
Systemic steroid use, even short-term, must not have been used within the month
prior to enrollment

10. Any medical condition (eg, congestive heart failure, coronary artery disease,
chronic obstructive pulmonary disease, severe osteoarthritis, poorly controlled
asthma) that would make the study procedures risky for the participant (e.g.
exercise-induced angina and asthma) or that may confound the study results (e.g.
untreated obstructive sleep apnea, severe osteoarthritis).

11. Participation in a clinical protocol (e.g. anti-inflammatory drug intervention
study) which includes an intervention that may affect the results of the current
study.

12. Inability to perform the bicycling exercise task.

13. Clinically significant claustrophobia

14. Not willing to allow for research samples to be shared with other researchers.

15. Employees or staff at NIH that are directly supervised by the primary
investigator or associate investigators.

- Additional exclusion criteria for participants with PI-ME/CFS for phenotyping visit

1. Significant neurological disorder (e.g. neurodegenerative disorder, stroke,
epilepsy).

2. PI-ME/CFS disease severity that makes it impossible for the volunteer to leave
the home or requires inpatient treatment.

3. Suspected, probable, or confirmed Lyme disease per 2011 CDC Lyme Disease National
Surveillance Case Definitions.

4. Underlying illness that may cause fatigue such as thyroid dysfunction, hepatitis,
or other systemic diseases.

- Additional exclusion criteria for participants with PI-ME/CFS for exercise stress
visit

1. Current (within 1 week) use of prescription or over-the-counter medications, herbal
supplements, or nutraceuticals that may influence brain excitability that the
potential participant is either unwilling or clinically unable to safely wean off for
the duration of the period of the exercise stress visit. The possibility for a
potential participant to be weaned off medication will be cooperatively determined by
both the clinical investigative team and personal physicians. Examples of medications
that influence brain excitability include tricyclic antidepressants, hypnotic,
antiepileptic, antipsychotic medication, stimulants, antihistamines, muscle relaxants,
dopaminergic medications, and sleep medications.

- Additional exclusion criteria for healthy volunteer group

1. Substantial daily fatigue as determined using PROMIS-SF Fatigue: score of > 17.

2. Significant neurological disorder (e.g. neurodegenerative disorder, stroke,
epilepsy).

3. Current (within 1 week) use of prescription or over-the-counter medications,
herbal supplements, or nutraceuticals that may influence brain excitability

- Additional exclusion criteria for Documented Lyme Infection - Asymptomatic group

1. Substantial daily fatigue as determined using the Multidimensional Fatigue
Inventory (MFI): score of > 8 on the general fatigue subscale or >6 on the
reduced activity subscale.

2. Significant neurological disorder (e.g. neurodegenerative disorder, stroke,
epilepsy).

3. Symptoms or diagnosis of Post-Lyme Disease Syndrome

4. Current (within 1 week) use of prescription or over-the-counter medications,
herbal supplements, or nutraceuticals that may influence brain excitability