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Characterizing non-restorative sleep in post-viral disease to advance intervention innovations

Drs. Janet Mullington, Robert Thomas, Larissa Engert, Samuel Frank, Monika Haack, Jason Maley, Recep Ozdemir, Haoqi Sun, Alicia Stokes, John Torous, and Brandon M. Westover – Harvard Medical School and the Open Medicine Foundation-Supported Ronald G. Tompkins Harvard ME/CFS Collaboration

The goal of this project is to characterize several features of sleep regulation in ME/CFS and Long COVID compared with age and sex matched healthy sleep controls. The study will look at four primary components: 1) sleep-circadian dysfunction; 2) how immune function, specifically specialized pro-resolving mediators (SPMs), are changed in relation to sleep dysfunction; 3) brain electrical activity; and 4) mechanisms of state-boundary control and neurodegenerative diseases.

Systems Biology Approaches to Uncovering Disease Mechanism and Drug Repurposing for Long COVID

Dr. Wenzhong Xiao – Massachusetts General Hospital and the Open Medicine Foundation-Supported Computational Research Center for Complex Diseases

This project will use deep machine learning and network medicine to parse through clinical information, research findings, and multi-omics data of Long COVID, ME/CFS, and related diseases with the collective knowledge-base of drugs, diseases, genes, and symptoms to discover disease gene modules, and identify potential drugs as candidates for repurposing for these illnesses.

Multi-omic approAches to Solve post-Acute COVID-19/SARS-CoV-2 Syndrome

Prof. Alain Moreau – Université de Montréal and the Open Medicine Foundation-Supported ME/CFS Collaborative Center at CHU Sainte-Justine/Université de Montréal; Prof. Jonas Bergquist –the Open Medicine Foundation-Supported ME/CFS Collaboration at Uppsala University; Dr. Christopher Armstrong – Open Medicine Foundation-Supported Melbourne ME/CFS Collaboration; Dr. Wenzhong Xiao – Harvard University and the Open Medicine Foundation-Supported Computational Research Center for Complex Diseases; Dr. Dawei Li – Florida Atlantic University; and Dr. Tse Man Sze – Université de Montréal

This project hypothesizes that Long COVID, and ME/CFS after COVID, is the result of a broad molecular-level reorganization occurring primarily at the epigenetic level. The study aims to understand the molecular mechanisms underlying the development of long-term sequelae following a SARS-CoV-2 infection, by looking at 4 specific aims: 1) Global expression profiling of circulating microRNAs, 2) Global DNA methylation profiling, 3) Global proteomic plasma profiling, and 4) Global metabolomic plasma and urine profiling.

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CDC Update

The Centers for Disease Control and Prevention (CDC) recognizes the significant overlap between Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

According to the CDC, Long COVID, also known as Post-Acute Sequelae of SARS-CoV-2 infection (PASC), can include a range of long-term symptoms that persist for weeks or even months after recovery from the acute phase of COVID-19. These symptoms can include fatigue, cognitive impairment (often referred to as “brain fog”), sleep disturbances, and other symptoms that are also common in ME/CFS.

The CDC acknowledges that further research is needed to understand the relationship between Long COVID and ME/CFS, including whether or not a subset of people with Long COVID are developing ME/CFS.

OMF is committed to leading this critical research, with the goal of improving diagnostic tools, finding effective treatments, and ultimately, discovering a cure for these complex diseases.

In March 2020, OMF launched an international, multi-year study across the six OMF supported Collaborative Research Centers (CRC).  This was the first study of its kind and the aim is to examine the progression from COVID to Long COVID and the eventual progression to ME/CFS. 

  • Jonas Bergquist, MD, PhD
  • Wenzhong Xiao, PhD
  • Alain Moreau, PhD
  • Ronald W. Davis, PhD
  • Chris Armstrong, PhD
  • David Systrom, MD

In March 2020, OMF brought together its global collaborative network, across 6 research centers in 4 countries, to carry out this global effort in several stages, using an initial $1,000,000 grant donated 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 Long COVID and of those, the development of ME/CFS.

This data is also being 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 Long COVID, ME/CFS and other post-viral illnesses, identify potential diagnostic biomarkers and validate potential treatment targets for future clinical trials. 


  • 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 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 large cohort of patients currently report with post-COVID complications and two new clinics for seeing these patients have been opened in Uppsala.
  • 1500+ patients with initially less severe COVID but with severe sequelae and post-COVID complications are enrolled with surveys, plasma and blood
  • Surveys have been performed and first paper is submitted and under revision. 
  • Additional IRB has been filed to allow for blood sampling and RNA, proteomics and metabolomics and has now been approved.
  • Next Steps: RNA (in Ficoll isolated blood cells), Proteomics and Metabolomics (plasma) will be analyzed.
  • Clinical data are continuously compiled and will be sent to Computation Center for correlation with biomarkers.
  • First set of CSF samples from post-covid patients analyzed..

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.
Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS) Post Treatment Lyme Disease Syndrome (PTLDS), Fibromyalgia Leading Research. Delivering Hope.Open Medicine Foundation®

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