ME/CFS and Long Covid Research: 15 – 21 February 2022

February 25, 2022

The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).


The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.

Audio comments from Katrina Pears

ME/CFS Research Published 15 – 21 February 2022 

Research has certainly picked up again this week. There have been eight new ME/CFS studies and fourteen studies on Long Covid this week.  

We have highlighted two of these studies below:  

Paper one (1) is a urinalysis of mycotoxins in ME/CFS patients. The paper looks at 236 ME/CFS patients who have already identified an exposure to mould, unsurprisingly this results in evidence for exposure in 92.4% with Ochratoxin A (OTA) the most prevalent mycotoxin.  

There are clear gaps in this study, such as:  

  • patient selection (the study cohort already identifying mould exposure and with ME/CFS),  
  • no control groups,  
  • unknown prevalence of mould in the general population, 
  • patients were selected by those who could cover the costs of urinalysis testing through insurance or self-pay, 
  • second inclusion criteria was those exposed to water-damaged buildings, there are other pathways of being exposed to mould, 
  • therefore, it is hard to say from this study what levels are mycotoxins are critical and whether mycotoxins are a cause of ME/CFS. 

The authors say that this is a preliminary study, which was conducted with no funding, just the use of medical records. Furthermore, this study was to help initiate how control studies should be conducted in the future to investigate the association between chronic mould exposure and the diagnosis of ME/CFS. I do not feel this study adds anything we don’t already know, but highlights another gap in our knowledge and the need for more control studies. 

Paper three (3) looks at potential treatment options, focusing on restoring the supply of calcium (Ca2+) to natural killer cells (NK) which rely on it to function effectively. This study found that the use of naltrexone hydrochloride (NTX) restored the influx of calcium over-night in vitro (in a test tube). However, this study was small, only using 10 ME/CFS patients and 10 controls, and was conducted in vitro so we do not know how this treatment would translate into patients. Furthermore, we have previously seen very disappointing results for the use of low dose naltrexone (LDN) for ME/CFS (you can found more about this in a previous Research Summary here).  

This week there have also been two papers published on Orthostatic Intolerance (OI), which are papers four (4) and eight (8) (although the second paper is not directly related to ME/CFS). Paper four (4) examines hypocapnia (lowered CO2 in blood) which is present in a significant proportion of ME/CFS patients. Paper eight (8) explores the relationship between cardiovascular autonomic control, the orthostatic heart rate response, the amount of carbon dioxide (CO2) exhaled and the severity of orthostatic symptoms and fatigue in patients referred for evaluation of chronic OI. I don’t feel any of these papers tell us anything that is not already known about these conditions. 

You may also be interested in reading paper fourteen (14) in the Long Covid reference section, which is a book chapter on the use of melatonin for Covid management. As well as paper ten (10) which finds that vaccinated individuals are less likely to develop Long Covid

ME/CFS Research References and Abstracts  

1. Prevalence of Aspergillus-Derived Mycotoxins (Ochratoxin, Aflatoxin, and Gliotoxin) and Their Distribution in the Urinalysis of ME/CFS Patients 

Wu, T.Y.; Khorramshahi, T.; Taylor, L.A.; Bansal, N.S.; Rodriguez, B.; Rey, I.R.  
Int. J. Environ. Res. Public Health 2022, 19, 2052.  


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a known complex, multi-organ system disorder with a sudden or subacute onset. ME/CFS occurs most commonly among women between 30 and 50 years of age. The current diagnostic criteria of ME/CFS, as defined by the Centers for Disease Control and Prevention, includes: profound fatigue and post-exertional malaise (>6 mo) unrelieved by rest, persistent cognitive impairment or orthostatic intolerance, and chronic unrefreshing sleep.  

Despite reported associations between ME/CFS onset and exposure to infectious agents (viral, bacterial, or fungal), the pathophysiology of ME/CFS remains unknown.  

In this prevalence study, we investigated the rates of Aspergillus-derived toxin levels, Aflatoxin (AF), Ochratoxin A (OTA), and Gliotoxin (GT), in the urinalysis of 236 ME/CFS patients with a history of chronic exposure to mold (i.e., from water-damaged buildings).  

Among ME/CFS patients reporting chronic exposure to mold, we found evidence of exposure in 92.4 percent of patients, with OTA being the most prevalent mycotoxin. Mold distributions (OTA, AF, and GT) in the urinalysis all demonstrated right skewness, while the distribution of age of ME/CFS patients diagnosed showed no deviation from normality.  

This study aims to provide preliminary, epidemiological evidence among ME/CFS patients who were diagnosed in South Florida with a history of exposure to mycotoxins. Based on these findings, we proposed how future control studies should approach investigating the association between chronic mold exposure and the diagnosis of ME/CFS.  

2. Experiences of pain in paediatric chronic fatigue syndrome/myalgic encephalomyelitis: a single-centre qualitative study 

Serafimova T, Ascough C, Parslow RM, et al.  
BMJ Paediatrics Open 2022;6:e001201 


Background Moderate to severe pain affects up to two-thirds of children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and is associated with worse fatigue and physical functioning. This research aims to gain a greater insight into pain experienced by these children. 

Methods Thematic analysis of qualitative data from semistructured interviews with 13 children with CFS/ME (mean age=15.3 years, 67% female) was completed. 

Results Thematic analysis enabled construction of three themes: children’s wide-ranging experiences of pain, negative impact of pain and lack of effective treatment for pain and nine subthemes. The first theme demonstrated highly varied pain experiences, ranging from ‘like [being]… on fire’, like ‘being stabbed’ to ‘like…lead’. Children experienced pain in multiple sites and with wide-ranging frequency and severity.  

The second theme highlighted the profound negative impact of pain on multiple aspects of children’s lives. Physical activity was severely impaired; some children ‘couldn’t leave bed’ or ‘couldn’t…brush [their] own hair’. Abdominal pain meant some would ‘go…days without eating’. Pain substantially impacted on mental health, leaving children feeling ‘agitated’, experiencing ‘really bad panic attacks’ or making them ‘[want to] breakdown’. Children felt they ‘can’t do the things that everyone else can do’, had ‘missed out’ and are ‘behind everyone’. Some avoided socialising as they ‘don’t want to stop everyone else’.  

The final theme demonstrates the absence of adequate treatment for pain, with participants reporting ‘nothing has ever really got rid of it’ and only ‘slightly [takes] the edge off’ and other experiencing side effects. 

Conclusions Pain in paediatric CFS/ME is highly variable, common and often results in severe physical limitation and poor mental health. Effective treatments for pain represent an unmet need. 

3. Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients 

Eaton-Fitch, N., Du Preez, S., Cabanas, H. et al.  
J Transl Med 20, 94 (2022). 


Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious disorder of unknown aetiology. While the pathomechanism of ME/CFS remains elusive, reduced natural killer (NK) cell cytotoxic function is a consistent immunological feature. NK cell effector functions rely on long-term sustained calcium (Ca2+) influx. In recent years evidence of transient receptor potential melastatin 3 (TRPM3) dysfunction supports the hypothesis that ME/CFS is potentially an ion channel disorder. Specifically, reports of single nucleotide polymorphisms, low surface expression and impaired function of TRPM3 have been reported in NK cells of ME/CFS patients. It has been reported that mu (µ)-opioid receptor (µOR) agonists, known collectively as opioids, inhibit TRPM3. Naltrexone hydrochloride (NTX), a µOR antagonist, negates the inhibitory action of µOR on TRPM3 function. Importantly, it has recently been reported that NTX restores impaired TRPM3 function in NK cells of ME/CFS patients. 

Methods: Live cell immunofluorescent imaging was used to measure TRPM3-dependent Ca2+ influx in NK cells isolated from n = 10 ME/CFS patients and n = 10 age- and sex-matched healthy controls (HC) following modulation with TRPM3-agonist, pregnenolone sulfate (PregS) and TRPM3-antaognist, ononetin. The effect of overnight (24 h) NTX in vitro treatment on TRPM3-dependent Ca2+ influx was determined. 

Results: The amplitude (p < 0.0001) and half-time of Ca2+ response (p < 0.0001) was significantly reduced at baseline in NK cells of ME/CFS patients compared with HC. Overnight treatment of NK cells with NTX significantly improved TRPM3-dependent Ca2+ influx in ME/CFS patients. Specifically, there was no significance between HC and ME/CFS patients for half-time response, and the amplitude of Ca2+ influx was significantly increased in ME/CFS patients (p < 0.0001). 

Conclusion: TRPM3-dependent Ca2+ influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro. Collectively, these findings validate that TRPM3 loss of function results in altered Ca2+ influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS. 

4. Physiological assessment of orthostatic intolerance in chronic fatigue syndrome 

Natelson, B.H., Lin, JM.S., Blate, M. et al.  
J Transl Med 20, 95 (2022).  

Background: Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identified in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormality, followed by postural orthostatic tachycardia. 

Objective: Evaluate the physiologic response of patients with ME/CFS to a standardized OC. 

Design: Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2 ≤ 32 mmHg. Orthostatic tachycardia was heart rate increase ≥ 30 beats per minute compared with resting or ≥ 120 BPM. Orthostatic hypotension was decreased systolic pressure ≥ 20 mmHg from baseline. Tachypnea was respiratory rate of  ≥ 20 breaths per minute—either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2. 

Patients: 63 consecutive patients fulfilling the 1994 case definition for CFS underwent lean testing at first visit and then annually at visit 2 (n = 48) and 3 (n = 29). 

Measures: Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension. 

Results: The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not differ between those with and without hypocapnia. 

Conclusions: The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormality, hypocapnia, would be missed without capnography. 

5. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 2: Physiological Characteristics During Acute Exercise Are Abnormal in People With Postexertional Symptom Exacerbation 

Todd E. Davenport,  Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness 


No Abstract available- Full content available online 

6. Ginseng for the Treatment of Chronic Fatigue Syndrome: A Systematic Review of Clinical Studies 

Yang J, Shin K-M, Abu Dabrh AM, et al.  
Global Advances in Health and Medicine 


Background: Chronic fatigue syndrome (CFS) is a complex and often disabling chronic condition emerging worldwide, with no curative or definitive therapy yet identified. Ginseng has been widely used to treat fatigue in other patient groups and conditions; however, a systematic review focusing solely on the impact of ginseng on fatigue in patients with CFS has not been performed. 

Objective: This study aimed to assess the current state of evidence regarding ginseng for CFS. 

Methods: Multiple databases were searched from inception to October 2020. All data was extracted independently and in duplicates. Outcomes of interest included the effectiveness and safety of ginseng in patients with CFS. 

Results: 2 studies enrolling 68 patients were deemed eligible, including one randomized clinical trial and one prospective observational study. The certainty of evidence in the effectiveness outcome was low and moderate from both studies, while the safety evidence was very low as reported from one study. 

Conclusion: Study findings highlight a potential benefit of ginseng therapy in the treatment of CFS. However, we are not able to draw firm conclusions due to limited clinical studies. The paucity of data warrants limited confidence. There is a need for future rigorous studies to provide further evidence. 

7. Treatment of chronic fatigue syndrome from yangming meridian 

Xue KY, Cui J.  
Zhongguo Zhen Jiu. 2022 Feb 12;42(2):203-7. [Article in Chinese] 


Based on the theory of “brain-gut communication” and “heart-stomach disease simultaneously”, the thinking and method of treating chronic fatigue syndrome (CFS) from yangming meridian were discussed. CFS is related to brain and heart.  

Based on the analysis of meridian circulation, zangfu function and the indication characteristics of yangming meridian, the indications of yangming meridian are closely related to brain and heart, so it is proposed to start from yangming meridian and use Chinese herbs combined with acupuncture to treat CFS, including the four methods of clearing away heat and moisturizing dryness, cooling blood and removing blood stasis, promoting qi to clear the organs, and strengthening and replenishing deficiency.  

It has certain guiding and reference significance for clinical treatment of CFS. 

8. Cardiovascular Autonomic Regulation, ETCO 2 and the Heart Rate Response to the Tilt Table Test in Patients with Orthostatic Intolerance 

Wheeler C, Pacheco JM, Kim AC, Camacho-Santiago M, Kalafut MA, Ahern T, White AA, Patay B, Criado JR. 
Appl Psychophysiol Biofeedback. 2022 Feb 16. 


Chronic orthostatic intolerance (COI) is defined by changes in heart rate (HR), blood pressure (BP), respiration, symptoms of cerebral hypoperfusion and sympathetic overactivation.  

Postural tachycardia syndrome (POTS) is the most common form of COI in young adults and is defined by an orthostatic increase in heart rate (HR) of ≥ 30 bpm in the absence of orthostatic hypotension.  

However, some patients referred for evaluation of COI symptoms do not meet the orthostatic HR response criterion of POTS despite debilitating symptoms. Such patients are ill defined, posing diagnostic and therapeutic challenges.  

This study explored the relationship among cardiovascular autonomic control, the orthostatic HR response, EtCO2 and the severity of orthostatic symptoms and fatigue in patients referred for evaluation of COI.  

Patients (N = 108) performed standardized testing protocol of the Autonomic Reflex Screen and completed the Composite Autonomic Symptom Score (COMPASS-31) and the Fatigue Severity Scale (FSS).  

Greater severity of COI was associated with younger age, larger phase IV amplitude in the Valsalva maneuver and lower adrenal baroreflex sensitivity. Greater fatigue severity was associated with a larger reduction in ETCO2 during 10 min of head-up tilt (HUT) and reduced low-frequency (LF) power of heart rate variability.  

This study suggests that hemodynamic changes associated with the baroreflex response and changes in EtCO2 show a stronger association with the severity of orthostatic symptoms and fatigue than the overall orthostatic HR response in patients with COI. 

Long-COVID Research References   

  1. The autonomic aspects of the post-COVID19 syndrome 
  1. Neurological manifestations of long-COVID syndrome: a narrative review 
  1. ESCMID rapid guidelines for assessment and management of long COVID 
  1. Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study 
  1. ‘I can't cope with multiple inputs': a qualitative study of the lived experience of ‘brain fog' after COVID-19 
  1. Long-COVID: A growing problem in need of intervention 
  1. Lessons from Long COVID: working with patients to design better research 
  1. Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study 
  1. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus 
  1. Covid-19: Vaccinated people are less likely to get long covid, review finds 
  1. Pain Burden in Post-COVID-19 Syndrome following Mild COVID-19 Infection 
  1. Optimising cardiopulmonary rehabilitation of long COVID-19 syndrome: are we there yet? 
  1. COVID-19 and Mitochondrial Non-Coding RNAs: New Insights From Published Data 
  1. Melatonin as a multifactorial therapeutic strategy for covid-19 management 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent



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