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 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.'"

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".

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 as well as SEID and Reeves criteria. Positive Answers to Initial Questions re NIH Clinical Center Protocol - Comments Section - "Polly"

Funding
It is an intramural study being run within the National Institutes of Health facility, with no figure for funding given.

Ampligen
In March 2016, the National Institutes of Health met with Ampligen maker Hemispherx Biopharma.“Our recent meeting with Dr. 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.

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.

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bias", calls the study "a road map for proving psychosomatic causation of CFS" and calls for the study to be withdrawn.

Emeritus Professor Jonathan Edwards has criticised 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, Fred Gill, David Goldstein (neurocardiology), Mark Hallett (neurology & motor control), Wendy Henderson (gastrointestinal immunology), Silvina Horovitz (neurology & motor control), Steve Jacobson (virologist), Eunhee Kim, Mary Lee (psychoneuroendocrinology), Tanya Lehky (electromyography), Jon 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), 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.

Learn more

 * 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
 * 2016, NIH Pledges Long Term Effort on Chronic Fatigue
 * 2016, NIH - Solving ME/CFS will need an army of really good researchers working together
 * 2016, NIH March 8 2016 telebriefing presentations and protocol in a nutshell (ME Advocacy)
 * 2016, NIH telebriefing update & transcript of March 8th 2016 call
 * 2016, Community Report: ME/CFS Patients on Advice For the NIH Clinical Center Study
 * 2016, Patients' concerns about the study design
 * 2016, Extraordinary NIH ME/CFS study may be most comprehensive and in-depth ever
 * 2016, Solve ME/CFS Initiative Registers Major Concerns over NIH Study
 * 2016, NIH patient participation and communication - What do you want to see?
 * 2016, Solve ME/CFS Initiative - NIH Study
 * 2016, The Psychosomatic Researcher in the NIH's Big Chronic Fatigue Syndrome (ME/CFS) Study
 * 2016, NIH's initial response to comments and article on Walitt
 * 2016, Bad timing, says Collins of NIH response to CFSAC
 * 2016, CDC Grand Rounds - Chronic Fatigue Syndrome: Advancing Research and Clinical Education (Transcript 1, Transcript 2, Slides)
 * 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
 * 2015, Promises To Keep: NIH Commits to Reinvigorate Effort on Chronic Fatigue Syndrome