NIH Post-Infectious ME/CFS Study

The National Institutes of Health (NIH) announced in late 2015 its intention to begin an extensive study of 40 patients with "PI-ME/CFS" (Post-Infectious ME/CFS) in order to define subgroups, find biomarkers and identify treatments. The patients will 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
• Neuro-endocrine 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 cerebral spinal 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 cerebral spinal fluid."

• Cytokine & 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 immunomodulator

"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."

Selection criteria

• Documentation of acute infectious onset process
• Fatigue more than 6 months but less than 5 years
• Meet 1994 criteria and the Canadian Consensus Criteria

Results

The timing of results publication is unknown.

Criticism

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

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, Jeffrey Cohen (infectious disease & virology), Bart Drinkard, Luigi Ferrucci, Penny Friedman, Fred Gill, David Goldstein, Mark Hallett, Wendy Henderson, Silvina Horovitz, Steve Jacobson, Eunhee Kim, Mary Lee, Tanya Lehky, Johnathan Lyons, Eugene Major, Adriana Marques, Carine Maurer (neurologist), Joshua Milner, Leorey Saligan, Stephen Sinclair, Bryan Smith, Joseph Snow, Stacey Solin, Neal Young (immunologist), Jay Chung.

Patient advisory committee

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

Learn more

• 2016, CDC Grand Rounds - Chronic Fatigue Syndrome: Advancing Research and Clinical Education
• 2016, Response from Dr Nath about ACT-UP and patient involvement in research
• 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, Audio recording of CDC Grand Rounds event February 16
• 2016, Transcripts and slides from Dr Nath's talk on NIH study
• 2016, Chronic Fatigue Syndrome: Advancing Research and Clinical Education
• 2016, Three Pronged NIH ME/CFS Study Sets Treatments as Ultimate Goal
• 2016, The NIH Clinical Center Study for Chronic Fatigue Syndrome (ME/CFS): the Good, the Bad and the Just Plain Weird

See also

• National Institutes of Health
• Ian Lipkin
• Anthony Komaroff
• Charles Lapp
• Elizabeth Unger
• Avindra Nath

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.

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).

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.

cerebral 1. of or relating to the brain or the intellect 2. of, relating to, affecting, or being the cerebrum.

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

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.

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.

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

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.

immunologist A clinical immunologist is medical doctor specializing immune system problems that lead to infections, immunodeficiency disorders, autoimmune diseases, and autoinflammatory diseases including anaphylaxis ans allergies