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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" ([[Viral onset|Post-Infectious]] ME/CFS) in order to define [[Subtypes_of_ME/CFS#subgroups|subgroups of ME/CFS]], find [[diagnostic biomarker]]s and identify treatments.<ref name="NIHaction2015">{{Cite web|url=https://www.nih.gov/news-events/news-releases/nih-takes-action-bolster-research-myalgic-encephalomyelitis/chronic-fatigue-syndrome | title = NIH takes action to bolster research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2015-10-29 | website = [[National Institutes of Health]]|language=en|access-date=2020-06-26}}</ref> 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".<ref name="cdc_grand_rounds_talks">{{Cite web|url=https://www.meaction.net/2016/02/16/transcripts-and-slides-from-dr-naths-talk-on-nih-study/ | title = Transcripts and Slides from Dr Nath's talk on NIH study | date = 2016-02-16 | website = #MEAction|language=en-US|access-date=2020-06-26}}</ref> 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."<ref name="cdc_grand_rounds_talks" /> ====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".<ref name="cdc_grand_rounds_talks" /> *History and physical examination and systemic assessment *[[Nervous system|Neurological]] assessment *Neurocognitive assessment *[[Mental health|Psychiatric]] evaluation *[[Pain]]/[[headache]] evaluation *[[Infectious disease]] and rheumatologic evaluation by specialists *[[neuroendocrine symptoms|Neuroendocrine]] evaluation *[[Fatigue]] testing, [[Two day exercise test|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]]".<ref name="cdc_grand_rounds_talks" /> *[[Functional MRI]] *[[Metabolic]] studies *[[Transcranial magnetic stimulation]] *[[Autonomic nervous system|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]]."<ref name="cdc_grand_rounds_talks" /> *[[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 *[[:Category:Immunoglobulins|Immunoglobulin]] profile *[[Autoantibody|Autoantibodies]] directed against brain antigens *Cerebrospinal fluid [[proteomics]] and [[metabolomics]] *Gut and oral [[microbiome]] *Serum tryptase *[[virus|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."<ref name="cdc_grand_rounds_talks" /> *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."<ref name="cdc_grand_rounds_talks" /> ===Phase 3 - Evaluate immunomodulators=== "To conduct an early phase intervention study with an immunomodulatory agent that targets biomarkers found in Phase 2."<ref name="cdc_grand_rounds_talks" /> ==Patient recruitment== <blockquote>"...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 [[Elizabeth Unger|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 [[Fukuda criteria|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 [[Chronic lyme disease|Post Lyme Disease]] patients who are asymptomatic – that means they do not have fatigue and 20 patients with [[Functional movement disorder]]s."<ref name="cdc_grand_rounds_talks" /></blockquote> <blockquote>"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."<ref name="eligible2016">{{Cite web|url=https://www.nih.gov/mecfs/eligibility-requirements-me/cfs-clinical-study-nih | title = Eligibility Requirements for ME/CFS Clinical Study at the NIH | date = 2016-02-13 | website = National Institutes of Health (NIH)|language=EN|access-date=2020-06-26}}</ref></blockquote> === 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 disorder]]s in this study".<ref>{{Cite web|url=https://www.meaction.net/2016/03/03/extraordinary-nih-mecfs-study-may-be-most-comprehensive-and-in-depth-ever/ | title = Extraordinary NIH ME/CFS study may be most comprehensive and in-depth ever | date = 2016-03-03 | website = #MEAction|language=en-US|access-date=2020-06-26}}</ref> The initial requirement involving the [[Reeves criteria]] was dropped, and patients would only need to meet the [[Fukuda criteria|Fukuda]] or [[Canadian Consensus Criteria]] - not both - although they must have [[post-exertional malaise]].<ref name="eligible2016" /><ref>{{Cite web|url=https://www.meaction.net/2016/02/09/positive-answers-to-initial-questions-re-nih-clinical-center-protocol/ | title = Positive Answers to Initial Questions re NIH Clinical Center Protocol {{!}} Polly | last = | first = | authorlink = | date = 2016-02-09 | website = #MEAction|language=en-US|archive-url=|archive-date=|access-date=2020-06-26}}</ref><ref name="CTOct2020">{{Cite web | last = National Institute of Neurological Disorders and Stroke | date = 2020-10-03 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://clinicaltrials.gov/ct2/show/NCT02669212}}</ref> ===Selection criteria=== *Documentation of acute infectious onset process<ref name="CTSS2020">{{Cite web|url=https://mecfs.ctss.nih.gov/ | title = ME/CFS Clinical Trials Survey System | last = | first = | authorlink = | date = |website=mecfs.ctss.nih.gov|archive-url=|archive-date=|access-date=2020-06-26}}</ref> *ME/CFS with [[post-exertional malaise]]<ref name="CTOct2020" /> *Fatigue more than 6 months but less than 5 years<ref name="CTSS2020" /> *Meet [[Fukuda criteria | 1994 Fukuda criteria]] or the [[Canadian Consensus Criteria]].<ref name="CTOct2020" /> *Ages 18-60 only.<ref name="CTOct2020" /> ==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.<ref name="CTOct2020" /> ==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 ME/CFS Working Group|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]].<ref>{{Cite news | url=http://www.streetinsider.com/Corporate+News/Hemispherx+Biopharma+(HEB)+Comments+on+Recent+Meeting+with+NIH+for+MECFS+Research+Advancement/11408291.html | title = Hemispherx Biopharma (HEB) Comments on Recent Meeting with NIH for ME/CFS Research Advancement | last = | first = | date = 2016 | work=StreetInsider.com|access-date=2020-06-26|archive-url=|archive-date=|quote=}}</ref> {{See also|Ampligen}} ==Publications== * 2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Stussman2020">{{Cite journal | last = Stussman | first = Barbara | authorlink = Barbara Stussman | last2 = Williams | first2 = Ashley | authorlink2 = | last3 = Snow | first3 = Joseph | authorlink3 = Joseph Snow | last4 = Gavin | first4 = Angelique | authorlink4 = | last5 = Scott | first5 = Remle | authorlink5 = | last6 = Nath | first6 = Avindra | authorlink6 = Avindra Nath | last7 = Walitt | first7 = Brian | authorlink7 = Brian Walitt | date = 2020 | title = Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://doi.org/10.3389/fneur.2020.01025 (Full text)] * 2019, Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations<ref name="Mandarano2019">{{Cite journal | last = Mandarano | first = Alexandra H. | authorlink = Alexandra Vink-Niese | last2 = Maya | first2 = Jessica | authorlink2 = | last3 = Giloteaux | first3 = Ludovic | author-link3 = Ludovic Giloteaux | last4 = Peterson | first4 = Daniel L. | authorlink4 = Daniel Peterson | last5 = Maynard | first5 = Marco | authorlink5 = | last6 = Gottschalk | first6 = C. Gunnar | authorlink6 = Gunnar Gottschalk | last7 = Hanson | first7 = Maureen R. | authorlink7 = Maureen Hanson | date = 2020-03-02 | title = Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations|url=https://www.jci.org/articles/view/132185|journal=The Journal of Clinical Investigation|language=en|volume=130|issue=3|pages=1491–1505|doi=10.1172/JCI132185|issn=0021-9738|pmc=7269566|pmid=31830003|access-date=|quote=|via=}}</ref> - [https://www.jci.org/articles/view/132185 (Full text)] ==NIH announcements== *Dec 12, 2019, [https://www.nih.gov/news-events/news-releases/study-finds-differences-energy-use-immune-cells-me/cfs Study finds differences in energy use by immune cells in ME/CFS] *Aug 20, 2019, [https://www.ninds.nih.gov/About-NINDS/Who-We-Are/Advisory-Council/MECFS-Working-Group/Responses-Request-Information-Soliciting 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 model|biopsychosocial]] illness model of ME/CFS. Other concerns have been expressed regarding patient inclusion and exclusion criteria and the inclusion of two controversial entities ([[chronic Lyme disease|post-treatment Lyme]] and functional movement disorder) as control arms in the study - although the functional movement disorder group was later removed.<ref name="PR43076" /> American patient group [[ME Advocacy]] accused the [[National Institutes of Health]] of "continued [[research bias in ME/CFS|institutional bias]]", calling the study "a road map for proving psychosomatic causation of CFS" and calls for the study to be withdrawn.<ref>{{Cite web|url=https://www.meadvocacy.org/nih_clinical_study_a_case_of_continued_institutional_bias | title = NIH Clinical Study: A Case of Continued Institutional Bias | last = | first = |website=[[ME Advocacy]]|access-date=2020-06-26}}</ref><ref>{{Cite web|url=https://www.meadvocacy.org/further_analysis_of_nih_clinical_cfs_study | title = Further Analysis of NIH Clinical CFS Study | last = | first = | last2 = | first2 = |website=[[ME Advocacy]]|access-date=2020-06-26}}</ref> 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.<ref name="PR43076">{{Cite web|url=https://forums.phoenixrising.me/threads/details-on-nih-study.43076/ | title = Details on NIH study | website = Phoenix Rising ME/CFS Forums|language=en-US|access-date=2020-06-26}}</ref> [[Carol Head]] of the [[Solve ME/CFS Initiative]] said she was "deeply troubled by [[Brian Walitt|Dr Walitt's]] comments".<ref>{{Cite web|url=https://twitter.com/plzsolvecfs/status/701826226424426496 | title = plzsolvecfs status 701826226424426496 | last = Head | first = Carol | authorlink=Carol Head | date = |website=Twitter|language=en|archive-url=|archive-date=|access-date=2020-06-26}}</ref> [[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.<ref>{{Cite web|url=https://www.meaction.net/2016/03/04/meactions-questions-for-nihs-intramural-study-team/ | title = #MEAction's Questions for NIH's Intramural Study Team | date = 2016-03-04 | website = #MEAction|language=en-US|access-date=2020-06-26}}</ref> It also suggested patients sign a petition encouraging the NIH to include patients at the center of the study design.<ref>[http://my.meaction.net/petitions/nih-put-me-cfs-patients-at-heart-of-research-design-process NIH: Put ME/CFS patients at the heart of the research design process]</ref> 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".<ref>{{Cite web|url=http://slightlyalive.blogspot.com/2016/03/an-open-letter-to-dr-collins-and-dr.html | title = Slightly Alive: An Open Letter to Dr. Collins and Dr. Nath on the NIH internal ME/CFS study | last = Schweitzer | first = Mary | date = 2016-03-04 | website = Slightly Alive|access-date=2020-10-11}}</ref> ==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<ref name="GrandRound2016">{{Cite web|url = https://www.cdc.gov/cdcgrandrounds/pdf/archives/2016/feb2016.pdf | page = 54 | last = Centers for Disease Control | first = | authorlink = Centers for Disease Control | title = CDC Grand Rounds February 2016 | date = Feb 2016}}</ref>: <div style="column-count:2"> *[[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 cell]]s, 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) </div> ==Patient advisory committee== There will be a committee of patients, but its members and role are not clear.<ref name="cdc_grand_rounds_talks" /> ==News coverage and interviews == *May 3, 2017, [https://www.nbcnews.com/health/health-news/nih-study-takes-deepest-dive-yet-baffling-condition-n754271 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, [https://www.meaction.net/2022/05/04/nih-research-update/ Research Update: The NIH Intramural ME/CFS Study] - MEAction *[https://clinicaltrials.gov/ct2/show/NCT02669212 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Clinical trial NCT02669212] - updated Oct 3, 2020 *[http://mecfs.ctss.nih.gov/ NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Study] *[http://mecfs.ctss.nih.gov/faq.html NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Study - Frequently Asked Questions] *[http://www.medpagetoday.com/Neurology/GeneralNeurology/56772 NIH Gears Up For First Ever Chronic Fatigue Study] - Medpage Today *2017, [http://simmaronresearch.com/2017/07/the-fishing-expedition-report-from-the-nih-intramural-study-on-mecfs/ The Big Fishing Expedition: Report From the NIH Intramural Study on ME/CFS] *2016, [http://solvecfs.org/NIH+Begins+Recruitment+of+ME/CFS+Study+Participants Solve ME/CFS Initiative Registers Major Concerns over NIH Study] *2016, [http://www.cortjohnson.org/forums/threads/the-psychosomatic-researcher-in-the-nihs-big-chronic-fatigue-syndrome-me-cfs-study.3757/ The Psychosomatic Researcher in the NIH's Big Chronic Fatigue Syndrome (ME/CFS) Study] *2016, [https://www.youtube.com/watch?v=0SnJy5AOSd8/ Video of CDC Grand Rounds 16-Feb - Chronic Fatigue Syndrome: Advancing Research and Clinical Education] *2016, [https://www.youtube.com/watch?v=hRdn4A2SGic/ Video of CDC Beyond the Data – Chronic Fatigue Syndrome: Advancing Research and Clinical Education] *2016, [http://www.cdc.gov/cdcgrandrounds/archives/2016/february2016.htm Chronic Fatigue Syndrome: Advancing Research and Clinical Education] * 2016, [http://www.meaction.net/2016/04/27/nih-study-will-bring-new-technology-and-expertise-to-mecfs/ 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]] ==References== {{Reflist}} [[Category:Notable studies]] [[Category:Research initiatives]] [[Category:American research initiatives]]
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