NIH Post-Infectious ME/CFS Study

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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.[1] The patients will 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]

  • 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)[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 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 cerebralspinal fluid."[2]

  • 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[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]

  • 2019, Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations[9] - (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. 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 - although the functional movement disorder group was later removed.[10]

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.[11][12]

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.[10]

Carol Head of the Solve ME/CFS Initiative said she was "deeply troubled by Dr Walitt's comments".[13]

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

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".[16]

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[17]:

Patient advisory committee[edit | edit source]

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

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 (NIH). Oct 29, 2015. Retrieved Jun 26, 2020. 
  2. 2.02.12.22.32.42.52.62.72.82.9 "Transcripts and Slides from Dr Nath's talk on NIH study". #MEAction. Feb 16, 2016. Retrieved Jun 26, 2020. 
  3. 3.03.1 "Eligibility Requirements for ME/CFS Clinical Study at the NIH". National Institutes of Health (NIH). Feb 13, 2016. Retrieved Jun 26, 2020. 
  4. "Extraordinary NIH ME/CFS study may be most comprehensive and in-depth ever". #MEAction. Mar 3, 2016. Retrieved Jun 26, 2020. 
  5. "Positive Answers to Initial Questions re NIH Clinical Center Protocol | Polly". #MEAction. Feb 9, 2016. Retrieved Jun 26, 2020. 
  6. 6.06.16.26.36.4 National Institute of Neurological Disorders and Stroke (NINDS) (Oct 3, 2020). "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome". 
  7. 7.07.1 "ME/CFS Clinical Trials Survey System". mecfs.ctss.nih.gov. Retrieved Jun 26, 2020. 
  8. "Hemispherx Biopharma (HEB) Comments on Recent Meeting with NIH for ME/CFS Research Advancement". StreetInsider.com. 2016. Retrieved Jun 26, 2020. 
  9. Mandarano, Alexandra H.; Maya, Jessica; Giloteaux, Ludovic; Peterson, Daniel L.; Maynard, Marco; Gottschalk, C. Gunnar; Hanson, Maureen R. (Mar 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 7269566Freely accessible. PMID 31830003. 
  10. 10.010.1 "Details on NIH study". Phoenix Rising ME/CFS Forums. Retrieved Jun 26, 2020. 
  11. Feb 09, 2016. "NIH Clinical Study: A Case of Continued Institutional Bias". MEadvocacy.org. Retrieved Jun 26, 2020. 
  12. Feb 10, 2016; Reactions, 4. "Further Analysis of NIH Clinical CFS Study". MEadvocacy.org. Retrieved Jun 26, 2020. 
  13. Head, Carol. "plzsolvecfs status 701826226424426496". Twitter. Retrieved Jun 26, 2020. 
  14. "#MEAction's Questions for NIH's Intramural Study Team". #MEAction. Mar 4, 2016. Retrieved Jun 26, 2020. 
  15. NIH: Put ME/CFS patients at the heart of the research design process
  16. Schweitzer, Mary (Mar 4, 2016). "Slightly Alive: An Open Letter to Dr. Collins and Dr. Nath on the NIH internal ME/CFS study". Slightly Alive. Retrieved Oct 11, 2020. 
  17. Centers for Disease Control (Feb 2016). "CDC Grand Rounds February 2016" (PDF). p. 54. 

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.

ME/CFS - An acronym that combines myalgic encephalomyelitis with chronic fatigue syndrome. Sometimes they are combined because people have trouble distinguishing one from the other. Sometimes they are combined because people see them as synonyms of each other.

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.

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

metabolomics - The analysis of the chemical metabolism within cells, tissues or organisms. The term is often used to refer to the full set of metabolites found in a cell in a given environment.

T cell - A type of white blood cell which is mostly produced or matured in the thymus gland (hence T-cell) and is involved in the adaptive immune response on a cellular level. Also known as a T lymphocyte. (Learn more: www.youtube.com)

antibody - Antibodies or 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.)

antibody - Antibodies or 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 - 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.

Canadian Consensus Criteria (CCC) - A set of diagnostic criteria used to diagnose ME/CFS, developed by a group of practicing ME/CFS clinicians in 2003. The CCC is often considered to be the most complex criteria, but possibly the most accurate, with the lowest number of patients meeting the criteria. Led to the development of the International Consensus Criteria (ICC) in 2011.

post-exertional malaise (PEM) - A notable exacerbation of symptoms brought on by small physical or cognitive 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.

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.

myalgic encephalomyelitis (ME) - 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.

bias - Bias in research is "a systematic deviation of an observation from the true clinical state".

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. Although "Somatic Symptom Disorder" is the term used by DSM-5, the term "Bodily Distress Disorder" has been proposed for ICD-11. (Learn more: www.psychologytoday.com)

chronic fatigue syndrome (CFS) - A fatigue-based illness. The term CFS was invented invented by the U.S. Centers for Disease Control as an replacement for myalgic encephalomyelitis (ME). Some view CFS as a neurological disease, others use the term for any unexplained long-term fatigue. Sometimes used as a the term as a synonym of myalgic encephalomyelitis, despite the different diagnostic criteria.

The information provided at this site is not intended to diagnose or treat any illness.
From MEpedia, a crowd-sourced encyclopedia of ME and CFS science and history.