NIH Post-Infectious ME/CFS Study

The National Institutes of Health Intramural Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Study or NIH Post-Infectious ME/CFS Study or NIH Intermural Research Program was announced in late 2015, its intention was to begin an extensive study of 40 patients with "PI-ME/CFS" (Post-Infectious ME/CFS) in order to define subgroups of ME/CFS, find diagnostic biomarkers and identify treatments. The patients were to be selected from seven clinical sites around the United States.

Aims

Doctor Avindra Nath stated "The relationship of infections to the onset of ME/CFS and the large body of literature identifying a variety of interesting but inconsistent immune abnormalities in these patients provide a rationale for further studies of immune regulation". The study is designed to form three phases:

Phase 1 - Deep phenotyping

"To conduct a cross-section study for deep phenotyping of PI-ME/CFS to define its pathophysiology."

Aim 1 - To define the clinical phenotype

"...the first aim of this study is to define the clinical phenotyping using in-depth assessments of all domains of the illness".

• History and physical examination and systemic assessment
• Neurological assessment
• Neurocognitive assessment
• Psychiatric evaluation
• Pain/headache evaluation
• Infectious disease and rheumatologic evaluation by specialists
• Neuroendocrine evaluation
• Fatigue testing, exercise capacity

Aim 2 - To understand the underlying physiology of fatigue (pre and post-exercise)

"Aim two of the study is to define the physiological basis of fatigue using functional MRI scan of the brain to define the brain circuits that are involved. Do detailed metabolic studies in a metabolic chamber and do transcranial magnetic stimulation as well as very detailed autonomic testing. Each of these tests will be performed before and after exercise".

• Functional MRI
• Metabolic studies
• Transcranial magnetic stimulation
• Autonomic function

Aim 3 - To determine if there are abnormal immune or microbiome profiles

"The third aim of this study is to conduct a detailed immunological study in blood as well as cerebrospinal fluid including a screen for autoantibodies to neuro antigens. We will also fully explore the gut and oral microbiome and apply proteomics and metabolomics approaches to the cerebrospinal fluid."

• Cytokine abd chemokine profile in cerebrospinal fluid and blood; after T cell stimulation in culture
• Flow cytometry
• B cell and T cell cloning and T cell antigen receptor sequencing
• Immunoglobulin profile
• Autoantibodies directed against brain antigens
• Cerebrospinal fluid proteomics and metabolomics
• Gut and oral microbiome
• Serum tryptase
• Viral discovery, antibodies to herpes virus

Aim 4 - To determine if features can be reproduced in ex-vivo studies

"The fourth aim of this study will utilize a variety of novel approaches to explore whether cells or serum from patients can be used to experimentally reproduce some of the features of the illness. We will determine if there is an inherent metabolic abnormality in neurons derived from stem cells and culture from these patients and if exposure of spinal fluid will induce the functional abnormalities in these cells. We will also generate humanized mice using blood cells from patients and determine if the clinical phenotype can be reproduced in these animals. If these experimental systems are able to reproduce the clinical or biological abnormalities seen in these patients, it would be a major step towards identifying the cause and the pathophysiology of the illness and for developing a variety of treatment approaches to these patients."

• To determine if there are functional or mitochondrial abnormalities and electrophysiological properties in induced pluripotent stem cell (iPS) derived neurons from patients with PI-ME/CFS.
• Effect of serum and cerebrospinal fluid on iPS cells and derived neurons.
• To determine if cerebrospinal fluid or antibodies injected in brains of rodents or humanized mice generated with cells from PI-ME/CFS patients can lead to fatigue or behavioral abnormalities.

Phase 2 - Establish biomarkers

"To validate select biomarkers from Phase 1 in a longitudinal study and establish objective endpoints for an intervention study."

Phase 3 - Evaluate immunomodulators

"To conduct an early phase intervention study with an immunomodulatory agent that targets biomarkers found in Phase 2."

Patient recruitment

"...for the purpose of our phase one study, we plan to recruit patients primarily from well characterized cohorts– particularly the CDC’s M CAM study described earlier by Dr Unger. Selection criteria will include documentation of the acute onset and duration of fatiguing illness for more than 6 months but less than five years. All patients will have post-exertional malaise and full criteria of the 1994 research case definition and the Canadian Consensus Criteria as mentioned earlier. The study population will include 40 Post infectious ME/CFS patients, 20 healthy controls, 20 Post Lyme Disease patients who are asymptomatic – that means they do not have fatigue and 20 patients with Functional movement disorders."

"The eligibility criteria for this study includes four groups of adults that either: 1) have ME/CFS with post-exertional malaise fulfilling multiple consensus criteria; 2) had Lyme disease, were treated, and don't have fatigue symptoms; 3) have a functional movement disorder; or 4) are healthy volunteers."

Changes

In March 2016, Vicky Whittemore confirmed a change to the recruitment criteria, stating "it has been decided that they will not include individuals with functional movement disorders in this study". The initial requirement involving the Reeves criteria was dropped, and patients would only need to meet the Fukuda or Canadian Consensus Criteria - not both - although they must have post-exertional malaise.

Selection criteria

• Documentation of acute infectious onset process
• ME/CFS with post-exertional malaise
• Fatigue more than 6 months but less than 5 years
• Meet 1994 Fukuda criteria or the Canadian Consensus Criteria.
• Ages 18-60 only.

Funding

It is an intramural study being run within the National Institutes of Health facility, with no figure for funding given. It is sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). The clinical trial number is NCT02669212.

Ampligen

In March 2016, the National Institutes of Health met with Ampligen maker Hemispherx Biopharma.“Our recent meeting with Dr. Walter Koroshetz and members of the Trans NIH working group allowed us to review Ampligen® studies to date and discuss how the NIH’s research may assist us in closing key questions from the FDA,” said Thomas K. Equels, CEO of Hemispherx Biopharma.

See also

Ampligen.

Publications

• 2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - (Full text)
• 2019, Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations - (Full text)

NIH announcements

• Dec 12, 2019, Study finds differences in energy use by immune cells in ME/CFS
• Aug 20, 2019, Responses to Request for Information: Soliciting Input on How Best to Advance Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research

Criticism

Some patients have expressed concern at investigator Doctor Brian Walitt being a proponent of the biopsychosocial illness model of ME/CFS. Other concerns have been expressed regarding patient inclusion and exclusion criteria and the inclusion of two controversial entities (post-treatment Lyme and functional movement disorder) as control arms in the study - although the functional movement disorder group was later removed.

American patient group ME Advocacy accused the National Institutes of Health of "continued institutional bias", calling the study "a road map for proving psychosomatic causation of CFS" and calls for the study to be withdrawn.

Emeritus Professor Jonathan Edwards has criticized the sample size in combination with the large number of tests performed, arguing that it is easy to miss something important with a cohort of 40, and that the large number of tests makes obtaining reliable statistics difficult.

Carol Head of the Solve ME/CFS Initiative said she was "deeply troubled by Dr Walitt's comments".

MEAction submitted a series of questions to the investigators following concerns raised about some aspects of the study, and some members of the study team. It also suggested patients sign a petition encouraging the NIH to include patients at the center of the study design.

Advocate and patient Mary Schweitzer criticized the study for not properly taking into account the history of the disease or the small but experienced group of doctors already treating it, saying "once again NIH is going off on its own, as if we were never here at all".

Investigators

The principal investigator of the study is Doctor Avindra Nath and the lead clinical investigator is Doctor Brian Walitt. Professor Ian Lipkin (Columbia University) and Elizabeth Unger (Centers for Disease Control) are members of the executive committee.

The other investigators are:

• Ana Acevedo (physiatrist)
• Jeffrey Cohen (infectious disease & virology)
• Bart Drinkard (physical therapist)
• Luigi Ferrucci (geriatrician & epidemiologist)
• Penny Friedman (internal medicine)
• Fred Gill (internal medicine), David Goldstein (neurocardiology)
• Mark Hallett (neurology & motor control)
• Wendy Henderson (gastrointestinal immunology)
• Silvina Horovitz (neurology & motor control)
• Steve Jacobson (virologist)
• Eunhee Kim (biostatistics)
• Mary Lee (psychoneuroendocrinology)
• Tanya Lehky (electromyography)
• Jonathan Lyons‎ (allergy)
• Eugene Major (virologist)
• Adriana Marques (Lyme disease, virology)
• Carine Maurer (neurology & motor control)
• Joshua Milner (T cells, allergy)
• Leorey Saligan (cancer fatigue)
• Stephen Sinclair (psychologist)
• Bryan Smith (neurology)
• Joseph Snow (neuropsychologist)
• Stacey Solin (nurse practitioner, internal medicine group)
• Neal Young (immunology, bone marrow)
• Jay Chung (metabolism)

Patient advisory committee

There will be a committee of patients, but its members and role are not clear.

News coverage and interviews

• May 3, 2017, NIH Study Takes the Deepest Dive Yet Into Baffling Condition - NBC News, showing Brian Vastag during a tilt-table test in the study

Learn more

• May 4, 2022, Research Update: The NIH Intramural ME/CFS Study - MEAction
• Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Clinical trial NCT02669212 - updated Oct 3, 2020
• NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Study
• NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Study - Frequently Asked Questions
• NIH Gears Up For First Ever Chronic Fatigue Study - Medpage Today
• 2017, The Big Fishing Expedition: Report From the NIH Intramural Study on ME/CFS
• 2016, Solve ME/CFS Initiative Registers Major Concerns over NIH Study
• 2016, The Psychosomatic Researcher in the NIH's Big Chronic Fatigue Syndrome (ME/CFS) Study
• 2016, Video of CDC Grand Rounds 16-Feb - Chronic Fatigue Syndrome: Advancing Research and Clinical Education
• 2016, Video of CDC Beyond the Data – Chronic Fatigue Syndrome: Advancing Research and Clinical Education
• 2016, Chronic Fatigue Syndrome: Advancing Research and Clinical Education
• 2016, NIH study will bring new technology and expertise to ME/CFS - MEAction

See also

• National Institutes of Health
• CDC Multi-site Clinical Assessment of CFS
• Ian Lipkin
• Anthony Komaroff
• Charles Lapp
• Elizabeth Unger
• Avindra Nath
• Vicky Whittemore

myalgic encephalomyelitis (M.E.) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

See National Institutes of Health.

National Institutes of Health (NIH) - A set of biomedical research institutes operated by the U.S. government, under the auspices of the Department of Health and Human Services.

See myalgic encephalomyelitis.

See chronic fatigue syndrome.

Post-Infectious ME/CFS, a term used by NIH for the NIH Post-Infectious ME/CFS Study (Intramural ME/CFS Study) (Learn more: me-pedia.org)

PI-ME/CFS Post-Infectious ME/CFS, a term used by NIH for the NIH Post-Infectious ME/CFS Study (Intramural ME/CFS Study) (Learn more: me-pedia.org)

phase one A drug trial involving only a small group of humans, often healthy volunteers, to assess drug safety and side effects. Typically 20-80 participants, often using a comparison group.

physiological Concerning living organisms, such as cells or the human body.  Physio logical (as in physio) is not to be confused with psych ological (emotional stress).

Concerning living organisms, such as cells or the human body.  Physio logical (as in physio) is not to be confused with psych ological (emotional stress).

physiological Concerning living organisms, such as cells or the human body.  Physio logical (as in physio) is not to be confused with psych ological (emotional stress).

microbiome The full collection of microscopic organisms (especially bacteria and fungi) which are present in a particular environment, particularly inside the human body.

autoantibody An antibody that works against the body's own antigens, a hallmark of autoimmune diseases. Autoantibodies are the opposite of an antibodies.

serum The clear yellowish fluid that remains from blood plasma after clotting factors have been removed by clot formation. (Blood plasma is simply blood that has had its blood cells removed.)

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

The clear yellowish fluid that remains from blood plasma after clotting factors have been removed by clot formation. (Blood plasma is simply blood that has had its blood cells removed.)

serum The clear yellowish fluid that remains from blood plasma after clotting factors have been removed by clot formation. (Blood plasma is simply blood that has had its blood cells removed.)

mitochondria Important parts of the biological cell, with each mitochondrion encased within a mitochondrial membrane. Mitochondria are best known for their role in energy production, earning them the nickname "the powerhouse of the cell". Mitochondria also participate in the detection of threats and the response to these threats. One of the responses to threats orchestrated by mitochondria is apoptosis, a cell suicide program used by cells when the threat can not be eliminated.

phase two A trial involve patients to assess side effects and effectiveness for a particular clinical condition. Typically 100-300 patients.

phase three Last phase of clinical trials before a drug can be approved for public use. Whereas Phase one assesses basic safety, and Phase two assesses basic efficacy, Phase three uses many trial participants to fully assess both safety and efficacy, and overall benefit/risk.

immunomodulator An immunomodulator is a substance that affects the functioning of the immune system

immunomodulator An immunomodulator is a substance that affects the functioning of the immune system

A drug trial involving only a small group of humans, often healthy volunteers, to assess drug safety and side effects. Typically 20-80 participants, often using a comparison group.

phase one A drug trial involving only a small group of humans, often healthy volunteers, to assess drug safety and side effects. Typically 20-80 participants, often using a comparison group.

Centers for Disease Control and Prevention (CDC) - The Centers for Disease Control and Prevention is a U.S. government agency dedicated to epidemiology and public health. It operates under the auspices of the Department of Health and Human Services.

See Centers for Disease Control and Prevention.

myalgic encephalomyelitis (M.E.) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

cytokine any class of immunoregulatory proteins secreted by cells, especially immune cells. Cytokines are small proteins important in cell signaling that modulate the immune system. (Learn more: me-pedia.org)

somatic symptom disorder A psychiatric term to describe an alleged condition whereby a person's thoughts somehow cause physical symptoms. The actual existence of such a condition is highly controversial, due to a lack of scientific evidence. It is related to other psychiatric terms, such as "psychosomatic", "neurasthenia", and "hysteria". Older terms include "somatization", "somatoform disorder", and "conversion disorder". Such terms refer to a scientifically-unsupported theory that claims that a wide range of physical symptoms can be created by the human mind, a theory which has been criticized as "mind over matter" parapsychology, a pseudoscience.

See somatic symptom disorder.

tilt table test A diagnostic test to determine orthostatic intolerance or other forms of dysautonomia. The patient is strapped to a table and the table is tilted while the patient is monitored.