Project : Droplet Digital PCR For Evaluation Of Associations Between Human Herpesvirus Infection And ME/CFS, 2020, Cliff

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wigglethemouse

Senior Member (Voting Rights)
This study received significant funding from the US NIH but it doesn't seem a paper will be published. I'm guessing they only received funding for R21 to do feasibility work and that work allowed them to develop a test but only test a small cohort.

US NIH Project Description
Source : https://projectreporter.nih.gov/pro...dvalue=&ddsub=&cr=1&csb=default&cs=ASC&pball=
Project Summary
Our hypothesis is that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has a viral aetiology and that the characteristic persistent remitting and relapsing nature of the syndrome is the result of poorly controlled infection with one or more known viruses, possibly due to an underlying immune deficiency.

We further hypothesise that the causative viruses will be human herpesviruses as they have the key characteristics of being highly prevalent, giving rise to lifelong infections, and undergoing prolonged periods of dormancy/latency with periodic reactivation at times of stress or immune compromise.

Linking viral infections to ME/CFS has been difficult due to the cross-sectional nature of most epidemiological studies of this disease. Thus, although differences in prevalence of some viruses have been reported, causal inference is lacking.

We believe that the development of highly sensitive, specific and quantitative nucleic acid based tests for quantification of human herpesviruses in non-invasive samples (e.g. saliva, urine), will allow us to conduct large scale prospective studies that will provide robust evidence for or against a link between herpesvirus reactivation and ME/CFS.

The purpose of this R21 application is to conduct exploratory/ developmental work that will underpin future, large scale, epidemiological studies. Our specific objectives are:
1) To develop and validate highly sensitive and specific, quantitative digital droplet PCR (ddPCR) tests to detect all 8 human herpes viruses in blood and in more easily accessible biological samples (e.g. saliva, urine).
2) To use these assays to test samples from 250 ME/CFS cases, 200 healthy controls, and 50 controls with confirmed multiple sclerosis (MS), in the UK and Norwegian ME/CFS biobanks and look for associations between herpes virus infection, ME/CFS status and clinical parameters.
3) In a subset of virus positive and negative participants, to conduct a pilot study to monitor changes in herpesvirus viral load over time (monthly sampling) and correlate this with clinical and biological markers. This study is novel in that it will use highly sensitive and specific molecular assays to detect and very accurately quantify circulating viral loads from noninvasively collected samples.

When combined with our ongoing recruitment and follow up of ME/CFS cases and controls in the UK (funded by 1R01AI103629-01A1) and our collaboration with the Norwegian ME/CFS biobank, this study will allow us, for the very first time, to correlate virus infection and reactivation with remission and relapse of clinical symptoms. If our hypotheses are found to be supported by the evidence, this will offer insights in to the underlying pathophysiology of the disease and open up new avenues for treatment and management of ME/CFS.
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US NIH Project Funding
https://projectreporter.nih.gov/project_info_history.cfm?aid=9326134&icde=50995847
2016 $140,688
2017 $132,224

There are no papers listed in the Results section. Instead it seems results are listed in the Outcomes section. Rather than 500 participants as quoted above it seems only 46 people participated and they say a large scale study is needed next.

NIH Project Outcomes Listing
https://projectreporter.nih.gov/project_info_outcomes.cfm?aid=9326134&icde=50995847
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease which causes unexplained persistent or recurrent incapacitating fatigue, alongside various other symptoms including those related to the endocrine system, the immune system, the autonomic nervous system and neurocognition, as well as pain. The cause of ME/CFS is unknown, and there is no diagnostic test: instead patients are currently diagnosed based on clinical symptom criteria. The medical research literature includes many suggested infectious agent triggers for ME/CFS, but there is no consensus across all studies, possibly related to the fairly small studies conducted.

Members of the herpes virus family, which includes Epstein-Barr virus and cytomegalovirus, have often been implicated in ME/CFS: it is possible that infection with a herpes family virus, which is normally controlled in healthy individuals in long-term infections, is not properly achieved in people living with ME/CFS, leading to higher viral loads. However, most existing tests for herpes viruses are not sensitive enough to detect changes in viral load.

In this study we have
1) Developed sensitive and robust assays for nine herpes family virus members: Herpes Simplex Virus (HSV)-1, HSV-2, Varicella Zoster Virus, Epstein-Barr Virus, Cytomegalovirus, Human Herpes Virus (HHV) 6A, HHV-6B, HHV-7 and Kaposi Sarcoma Herpes Virus, to allow accurate quantification of viral load in clinical samples
2) Conducted a pilot study, recruiting people living with ME/CFS and collecting saliva and urine samples in a moderately easy manner, using the standard postal system
3) Characterised differences in the absolute viral loads of these herpes viruses in thirty people with ME/CFS compared to sixteen healthy control individuals, and how these are associated with symptom severity. This work provides the assays and proof-of-concept data to enable a large scale study to be conducted, to determine whether absolute levels of viral burden, rather than mere infection per se, underlie ME/CFS.
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The work was presented at the CMRC 2020 conference. I've not been able to watch yet (It is difficult for me to watch videos). It has been viewed only 135 times on YouTube so hopefully this post spreads more awareness.

The UK ME/CFS Biobank: virological and immunological participant characterisation from Dr Jackie Cliff, London School of Hygiene & Tropical Medicine
Code: 
https://youtu.be/52j0ivCIlQg
 
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Thanks for highlighting this @wigglethemouse.

I've had a quick listen. It didn't sound as though the team have found easily identified differences in herpes viral loads yet, but they have made a lot of progress in making studies like this feasible (with samples of urine and saliva posted; samples taken on good/bad days and aligned with symptom surveys; ability to extract pathogen DNA from the posted samples using droplet digital PCR which allows for good estimation of viral loads).

There are hints of interesting findings including about MAIT cells, but the samples at the time of the presentation were too small for conclusions to be made.

My conclusion was that this team sound as though they know what they are doing and they probably won't claim findings that aren't well based. So, I hope they get more funding and I look forward to hearing more from them.
 
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