I wrote up a draft submission, which I plan to upload tomorrow. I'd appreciate any comments if anyone has any.
Dear NIH,
Thank you for the opportunity to provide feedback on the ME/CFS research priorities. The patient community appreciates the renewed efforts the NIH has placed into ME/CFS and Long COVID research, including through the Intramural Program.
Patient engagement and input into research priorities is also much appreciated. I suggest in future partnering with the Science for ME forum to promote awareness of future consultations. Many of the more scientifically minded patients are members of the S4ME forum. I was not aware of this consultation until this week.
I have reviewed the list of priorities and am impressed by its thoroughness. The NIH should be commended for reaching out to global subject matter experts in developing this prioritisation plan. I apologise if any of my suggestions are already in the priorities list. I am not a scientist so may miss the implications of some of the existing priorities.
I suggest that the NIH use these scientists as peer reviewers in assessing future grant requests (where they have relevant expertise). Anecdotally, the patient community has heard stories of the NIH using peer reviewers who do not believe that ME/CFS is a biophysical illness or lack a understanding of the latest research. This has served to undermine patient confidence in the NIH. Conversely, an improved peer review process could restore hope and confidence to the patient community.
I note the discussion in various groups on identifying a biomarker. The NIH should investigate and validate a biomarker that has already been identified. Ron Davis' nanoneedle research correctly identified all ME/CFS patients and all healthy controls (Esfandyarpour et al, A nanoelectronics blood-based diagnostic biomarker for ME/CFS Proc Natl Acad Sci USA (2019)). This research has been replicated in the UK with ME/CFS patients, healthy controls and MS patients (though the results have not been published). The nanoneedle is designed to be a cheap diagnostic tool and it could be the biomarker that has long been sought.
The biological interpretation of these findings - what exactly it means that ME/CFS cells are stressed - is unclear. One explanation may be the Wirth/Scheibenbogen hypothesis. The NIH should investigate this hypothesis further (Wirth and Scheibenbogen 2020
https://pubmed.ncbi.nlm.nih.gov/32247028/)
Until a biomarker is identified, care has to be taken in ensuring that patient cohorts in trials have ME/CFS and not other fatiguing illnesses. The population indirectness issues with the GET trials, which mainly used outdated definitions of ME/CFS that did not include post-exertional malaise (PEM), are well known. Best practice trials now require patients to have PEM and be diagnosed with ME/CFS. But could a person who self-reports as having PEM be mistaken? The IOM report summarised the research, finding that 4 to 8% of healthy controls self-reported as having PEM (
https://www.ncbi.nlm.nih.gov/books/NBK284902/). Thus, population indirectness may remain a (smaller) issue even in patient cohorts diagnosed meeting the ICC or other modern definition of ME/CFS.
The NIH should investigate how trial design could overcome this issue. One way may be to ensure all patients undergo a 2 day CPET to verify their PEM objectively, but this is expensive and selects against more severe patients who cannot undergo a CPET. An alternative is to recruit a larger cohort of patients. The NIH should run 2 day CPETs in a large number of patients to identify the proportion of persons diagnosed with ME/CFS with self-reported PEM who do not have PEM as measured by CPET. The NIH should outline a methodology for calculating how many more patients are required. If e.g. 4% of patients do not have PEM, then how many more patients are required to ensure the trial has sufficient statistical power to overcome a population indirectness problem of this magnitude?
Another question is whether trials should exclude ME/CFS patients with depression and other co-morbidities. Depression is common as a result of ME/CFS and this could skew the studied patient population towards less severe patients. The NIH should investigate whether patients with and without depression differ on various measures.
The NIH should also engage in autopsy studies. Existing autopsy studies have identified persistence of various viruses in deceased ME/CFS patients, particularly the brain (see
https://me-pedia.org/wiki/Autopsy_in_Myalgic_Encephalomyelitis for an overview). Dr Chia has repeatedly found enteroviruses in stomach biopsies. Perhaps the NIH could also do autopsies or biopsies on the vagus nerve which has been implicated in ME/CFS as well as tissues, other nerves and the CNS. It appears that viral persistence cannot be identified through blood and urine samples - viruses have been found in the tissues of those whose blood and urine tested negatively (
)
Recent research in long covid showed that there is physical muscle damage after PEM (as identified by muscle biopsies). This study should be replicated in a cohort of ME/CFS patients. (Appelman et al 2023,
https://www.nature.com/articles/s41467-023-44432-3).
The NIH should also defund and cease any research into its effort preference hypothesis and remove Dr Wallit from any ME/CFS research. The test identifying "effort preference" in Wallit et al 2024 (
https://pubmed.ncbi.nlm.nih.gov/38383456/) was designed to measure anhedonia. It doesn't identify effort preference if patients face negative biophysical consequences for engaging in exertion (such as pressing a button repeatedly). Patient concerns about Dr Wallit are long-standing and predictions that he would attempt to psychologist ME/CFS have now been borne out. The paper would otherwise have been bolstered patient confidence in the NIH given that it replicated findings that show ME/CFS is a biophysical illness.
I note that one of the circulation research priorities includes "facilitat[ing] placebo-controlled clinical trials with repurposed drugs directed at the underlying circulatory pathophysiology, e.g., pyridostigmine, low dose naltrexone". LDN deserves attention as a separate priority given that it is one of the few treatments for ME/CFS. It has a broader application than just ameliorating circulatory pathophysiology. For example, the Griffith Uni research showing it helps with calcium ion channel dysfunction (e.g. Cabanas et al 2021
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313851/).
On a similar note, the NIH should run a placebo controlled RCT of low dose Abilify (see Crosby et al
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02721-9).
This submission reflects my personal views, but I acknowledge with gratitude the assistance of members of a ME/CFS Telegram social group with idea generation and research.
