Driving research of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS),
Post Treatment Lyme Disease Syndrome (PTLDS), Fibromyalgia and Post COVID .

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Long COVID to ME/CFS Study

Study AIM

OMF secured a $1 million grant to launch the first year of an international, multi-year study across the six OMF supported Collaborative Research Centers (CRC).  The aim of this study is to examine Long COVID transitioning to ME/CFS. 

LEAD INVESTIGATORS
  • Ronald W. Davis, PhD
  • Wenzhong Xiao, PhD
  • David Systrom, MD
  • Jonas Bergquist, MD, PhD
  • Alain Moreau, PhD
  • Chris Armstrong, PhD
STUDY HYPOTHESIS AND DESCRIPTION

OMF has brought together its global collaborative network, across 6 research centers to carry out this global effort in several stages, using a $1,000,000 grant made specifically for this effort. We are actively working to raise additional funding to continue this critical study.

Researchers are testing and analyzing data from individuals from the point of early COVID-19 illness through their recovery or prolonged illness state. This study has an opportunity to reveal what causes one to fully recover versus those at high risk of developing ME/CFS. 

This data will be compared to the OMF-Funded Post-Viral Complications in Herpes Simplex Encephalopathy (HSE) study data to provide another post-viral contrast. This study design offers the chance to elucidate precise pathological mechanisms of ME/CFS and other post-viral illnesses, uncomplicated by factors associated with the chronicity of the illness, the potential identification of diagnostic biomarkers and potential targets for the development of treatments for the future.

OBJECTIVES

  • Collect data throughout the longitudinal study
  • Identify markers in the gene expression that are predictive of lengthy recovery or prolonged illness
  • Analyze inflammation markers in blood plasma and cerebrospinal fluid
  • Analyze metabolomics through urine and blood plasma samples
  • Collate the array of biological data collected to determine early predictive markers of ME/CFS after a significant viral trigger.
  • Conduct a study of the global circulating microRNA expression profiles.
  • Perform global DNA methylation profiling.
  • Conduct epigenome-wide association analysis
UPDATES AND POTENTIAL

Updates from Phase 1

  • All initial post COVID omics studies (nucleic acids, proteins and metabolites in CSF and blood of COVID patients, and HSE) have been undertaken with datasets received from Uppsala, Harvard and Stanford.
  • Computational analysis of all data sets is underway and will be published when final.
  • Longitudinal sample collection will continue along with further analyses.

 

Updates from the Long Covid Clinic at Uppsala

  • A new clinic for patients reporting with Long COVID complications has been opened in Uppsala.* It will continue the work of the OMF-Funded MultiCenter Collaborative Study on COVID to ME/CFS progression.
  • 1500+ patients with initially less severe COVID but with severe sequelae and post-COVID complications are enrolled with surveys.
  • The clinic provides an opportunity to continue studying the disease process as it develops, and hopefully better understand ME/CFS.  A subset of the previously critically ill patients will be monitored for disease progression over time alongside non-critically ill Long Covid patients who will also visit the clinic for continuing symptoms.
  • An additional IRB has been approved to allow for blood sampling and RNA, proteomics and metabolomics.
  • Next Steps: RNA (in Ficoll isolated blood cells), Proteomics and Metabolomics (plasma) will be analysed.
  • Clinical data are continuously compiled and will be sent to the Computation Center for correlation with biomarkers.
  • As with Phase 1 of the study investigators will use genomics, proteomics, metabolomics, and immunology to recover as many immune cells as possible and to characterize their evolution to ME/CFS. Furthermore, we are studying the plasma and cerebrospinal fluid (CSF) to identify proteins and large molecules (e.g., antibodies) as well as small molecules that appear or disappear in association with the development of ME/CFS.

Latest Updates from Montreal

  • Development of an algorithm using our 11 microRNA diagnostic panel allowing the stratification of long COVID patients along different long-term sequelae trajectories:
    • ME, ME+FM or FM
    • Severe respiratory dysfunction
    • Neurological
    • Allergy-related 
  • BrainCheck neurocognitive evaluations prior and after the induction of PEM led us to stratify long COVID patients into four clusters using a machine-learning method.
  • Patients classified in cluster A and B exhibit a neurocognitive profile often seen in ME/CFS patients while long COVID patients in cluster C and D exhibit more often neurological sequelae.
  • Preliminary findings suggest that long COVID patients in cluster B exhibit a better recovery of their neurocognitive function than those in cluster A or C
  • Next Steps: Validate these findings in a larger cohort.

Latest Updates from the Computation Center

  • COVID study underway with omics data (nucleic acids, proteins, and metabolites in blood) and associated ICU clinical information received from Uppsala and Stanford. Data on the long-term outcomes of the patients will be received. 
  • Sequence analysis of viral RNA and DNA revealed EBV and HHV6 reactivations in ICU COVID patients.
  • Computational analysis identified early metabolites associated with patient outcomes in ICU.
  • Analysis of proteins in CSF of ICU patients, ME/CFS patients, and controls identified unique patterns in each group.
  • Further analysis will correlate omics patterns with long COVID.
Proteomics
The large-scale study of proteins, which are large, complex molecules that are required for structure, function, and regulation of the human body's tissues and organs.
Microvesicles and viral sequencing
Microvesicles are a type of extracellular vesicle that is released from the cell membrane. Vesicles are small, fluid-filled sacs or vacuoles within the body. Sequencing is a technique used to determine the exact sequence of bases (A, C, G, and T) in a DNA (or viral) molecule.
NMR Metabolomics
NMR (Nuclear Magnetic Resonance) is an instrument/tool used to perform metabolic studies, metabolic profiling, and metabolomics in biofluids and tissues for more than 40 years using magnetic fields. There is a very close connection between metabolic measurements and NMR. This connection has flourished because of NMR’s many unique strengths for characterizing complex mixtures’ chemical composition.
Autoantibodies
Antibodies that react with self-molecules and that occur in healthy individuals and are referred to as natural antibodies or autoantibodies.
Extracellular DNA for viral reactivation and Mitochondrial DNA
exDNA (extracellular DNA), exDNA is often secreted actively and is used to perform several tasks, thereby offering an attractive target or tool for biotechnological, medical, environmental, and general microbiological applications. Viruses are intracellular parasites that rely to a significant extent on the host cell for replication. Viral reactivation occurs when an active replication of the viral genome results in a lytic (degradation of the cell) infection characterized by the release of new progeny (descendant) virus particles.
Immune cell profiling
The immune system has many important regulatory roles in disease development and progression. Given the emergence of effective immune therapies, reliable predictors of response are needed. Immune cell profiling determines response by evaluating immune cell populations from treated and untreated samples. For our purposes, we will evaluate the white blood cell response to the viral infection using a process called “Cytof.”
Leukocyte Genomics
A leukocyte is a colorless cell circulating in the blood and body fluids and is involved in counteracting foreign substances and disease. A genome is all genetic material of an organism. Genomics is a biology field focusing on the structure, function, evolution, mapping, and editing of genomes. Therefore, leukocyte genomics is the study of all genetic material of leukocytes.
Metabolomics
Metabolomics is a way to study metabolism – that is, through measuring amounts of the metabolites (small molecules) produced by our bodies as we convert food into energy and other molecules that our cells need to survive. Metabolomics technology is ‘large-scale,’ meaning that several thousand metabolites can be measured from a single sample of e.g., blood or urine.
Micro RNA
Cells use Micro RNA to control whether a particular gene is making too much, too little or the normal amount of its protein at a particular time.