NIH Post-Infectious ME/CFS Study

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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.[1] The patients were to be selected from seven clinical sites around the United States.

Aims[edit | edit source]

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".[2] The study is designed to form three phases:

Phase 1 - Deep phenotyping[edit | edit source]

"To conduct a cross-section study for deep phenotyping of PI-ME/CFS to define its pathophysiology."[2]

Aim 1 - To define the clinical phenotype[edit | edit source]

"...the first aim of this study is to define the clinical phenotyping using in-depth assessments of all domains of the illness".[2]

Aim 2 - To understand the underlying physiology of fatigue (pre and post-exercise)[edit | edit source]

"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".[2]

Aim 3 - To determine if there are abnormal immune or microbiome profiles[edit | edit source]

"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."[2]

Aim 4 - To determine if features can be reproduced in ex-vivo studies[edit | edit source]

"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."[2]

  • 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[edit | edit source]

"To validate select biomarkers from Phase 1 in a longitudinal study and establish objective endpoints for an intervention study."[2]

Phase 3 - Evaluate immunomodulators[edit | edit source]

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

Patient recruitment[edit | edit source]

"...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."[2]

"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."[3]

Changes[edit | edit source]

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".[4] 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.[3][5][6]

Selection criteria[edit | edit source]

Funding[edit | edit source]

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.[6]

Ampligen[edit | edit source]

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.[8]

Publications[edit | edit source]

  • 2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome[9] - (Full text)
  • 2019, Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations[10] - (Full text)

NIH announcements[edit | edit source]

Criticism[edit | edit source]

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.[11]

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.[12][13]

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.[11]

Carol Head of the Solve ME/CFS Initiative said she was "deeply troubled by Dr Walitt's comments".[14]

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.[15] It also suggested patients sign a petition encouraging the NIH to include patients at the center of the study design.[16]

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".[17]

Investigators[edit | edit source]

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[18]:

Patient advisory committee[edit | edit source]

There will be a committee of patients, but its members and role are not clear.[2]

News coverage and interviews[edit | edit source]

Learn more[edit | edit source]

See also[edit | edit source]

References[edit | edit source]

  1. "NIH takes action to bolster research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome". National Institutes of Health. October 29, 2015. Retrieved June 26, 2020.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 "Transcripts and Slides from Dr Nath's talk on NIH study". #MEAction. February 16, 2016. Retrieved June 26, 2020.
  3. 3.0 3.1 "Eligibility Requirements for ME/CFS Clinical Study at the NIH". National Institutes of Health (NIH). February 13, 2016. Retrieved June 26, 2020.
  4. "Extraordinary NIH ME/CFS study may be most comprehensive and in-depth ever". #MEAction. March 3, 2016. Retrieved June 26, 2020.
  5. "Positive Answers to Initial Questions re NIH Clinical Center Protocol | Polly". #MEAction. February 9, 2016. Retrieved June 26, 2020.
  6. 6.0 6.1 6.2 6.3 6.4 National Institute of Neurological Disorders and Stroke (October 3, 2020). "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome".
  7. 7.0 7.1 "ME/CFS Clinical Trials Survey System". Retrieved June 26, 2020.
  8. "Hemispherx Biopharma (HEB) Comments on Recent Meeting with NIH for ME/CFS Research Advancement". 2016. Retrieved June 26, 2020.
  9. Stussman, Barbara; Williams, Ashley; Snow, Joseph; Gavin, Angelique; Scott, Remle; Nath, Avindra; Walitt, Brian (2020). "Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome". Frontiers in Neurology. 11. doi:10.3389/fneur.2020.01025. ISSN 1664-2295.
  10. Mandarano, Alexandra H.; Maya, Jessica; Giloteaux, Ludovic; Peterson, Daniel L.; Maynard, Marco; Gottschalk, C. Gunnar; Hanson, Maureen R. (March 2, 2020). "Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations". The Journal of Clinical Investigation. 130 (3): 1491–1505. doi:10.1172/JCI132185. ISSN 0021-9738. PMC 7269566. PMID 31830003.
  11. 11.0 11.1 "Details on NIH study". Phoenix Rising ME/CFS Forums. Retrieved June 26, 2020.
  12. "NIH Clinical Study: A Case of Continued Institutional Bias". ME Advocacy. Retrieved June 26, 2020.
  13. "Further Analysis of NIH Clinical CFS Study". ME Advocacy. Retrieved June 26, 2020.
  14. Head, Carol. "plzsolvecfs status 701826226424426496". Twitter. Retrieved June 26, 2020.
  15. "#MEAction's Questions for NIH's Intramural Study Team". #MEAction. March 4, 2016. Retrieved June 26, 2020.
  16. NIH: Put ME/CFS patients at the heart of the research design process
  17. Schweitzer, Mary (March 4, 2016). "Slightly Alive: An Open Letter to Dr. Collins and Dr. Nath on the NIH internal ME/CFS study". Slightly Alive. Retrieved October 11, 2020.
  18. Centers for Disease Control (February 2016). "CDC Grand Rounds February 2016" (PDF). p. 54.