Research: Genetic association study in ME/CFS

Posted on 03/30/2022 by wames

Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci, by Riad Hajdarevic, Asgeir Lande, Jesper Mehlsen, Anne Rydland, Daisy D Sosa, Elin B  Strand, Olav Mella, Flemming Pociot, Øystein Fluge, Benedict A Lie, Marte K Viken in Brain, Behavior, and Immunity Vol 102, May 2022, Pages 362-369 [doi.org/10.1016/j.bbi.2022.03.010]

 

Research highlights

  • Largest ME/CFS genetic study to date.
  • Three different cohorts totaling more than 2500 patients.
  • First Immunochip study in ME/CFS.
  • Possible implication of TPPP genetic region.

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date.

In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N=427), a Danish replication cohort (N=460) and a replication dataset from the UK biobank (N=2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/CFS risk loci displaying genome-wide significance.

In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P=8.5×10-7), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P= 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association with time will be verified in even larger cohorts.

Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.

Discussion – excerpt

Using genome-wide array data and large ME/CFS cohorts (>2900 patients in total), we have identified several chromosomal regions with suggestive ME/CFS associations that warrants follow-up in subsequent studies towards the future establishment of the first ME/CFS genetic risk loci at genome-wide significance…

Despite the current lack of large cohorts of phenotypically stringent and well-characterized ME/CFS patients, this study represents, to the best of our knowledge, the largest and most homogenous genetic study performed in ME/CFS so far. Ongoing projects like the DecodeME project (https://www.decodeme.org.uk) will enable future studies of larger and more powerful cohorts, which are warranted to produce the desired statistical power to definitively investigate the genetic architecture of ME/CFS.

In conclusion, we identified several potential risk loci for ME/CFS, which encourage further investigations. Future genetic studies should be performed in large cohorts of several thousand patients and strive to use strict and comprehensive phenotyping to enable analyses of homogenous sub-phenotypes.

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Research: Long-term C-19 sequelae in adolescents: the overlap with OI & ME/CFS

Posted on 03/28/2022 by wames

Long-term COVID 19 sequelae in adolescents: the overlap with orthostatic intolerance and ME/CFS, by Amanda K Morrow, Laura A Malone, Christina Kokorelis, Lindsay S Petracek, Ella F Eastin, Katie L Lobner, Luise Neuendorff & Peter C Rowe in Curr Pediatr Rep. 2022 Mar 9:1-14

 

Review abstract:

Purpose 

To discuss emerging understandings of adolescent long COVID or post-COVID-19 conditions, including proposed clinical definitions, common symptoms, epidemiology, overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance, and preliminary guidance on management.

Recent Findings

The recent World Health Organization clinical case definition of post-COVID-19 condition requires a history of probable or confirmed SARS-CoV-2 infection, with symptoms starting within 3 months of the onset of COVID-19. Symptoms must last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms of the post-COVID-19 condition include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction. These symptoms generally have an impact on everyday functioning.

The incidence of prolonged symptoms following SARS-CoV-2 infection has proven challenging to define, but it is now clear that those with relatively mild initial infections, without severe initial respiratory disease or end-organ injury, can still develop chronic impairments, with symptoms that overlap with conditions like ME/CFS (profound fatigue, unrefreshing sleep, post-exertional malaise, cognitive dysfunction, and orthostatic intolerance).

Summary

We do not yet have a clear understanding of the mechanisms by which individuals develop post-COVID-19 conditions. There may be several distinct types of long COVID that require different treatments. At this point, there is no single pharmacologic agent to effectively treat all symptoms. Because some presentations of post-COVID-19 conditions mimic disorders such as ME/CFS, treatment guidelines for this and related conditions can be helpful for managing post-COVID-19 symptoms.

Conclusion

Emerging data confirm that prolonged symptoms can develop following even mild or asymptomatic initial SARS-CoV-2 infection. The most common symptoms are fatigue, cognitive dysfunction, and headaches. As ascertainment for orthostatic intolerance in these patients improves, lightheadedness is becoming more commonly recognized. A proportion of long COVID patients meet the criteria for ME/CFS at 6 months. At present, management of post-COVID conditions focuses primarily on addressing symptoms, borrowing management strategies from conditions like OI and ME/CFS.

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WAMES AGM 11 April 2022

Posted on 03/23/2022 by wames

WAMES Annual General Meeting

 

WAMES will be holding our annual business meeting via Skye on Monday 11th April at 4pm. This is the opportunity for members to elect officers, oversee the finances and identify priorities for the coming year.

If you would like to become a member of WAMES and help us keep on course with our mission – to be the voice of people affected by ME in Wales – please contact Sharon sharon@wames.org.uk

She will also be happy to discuss any of our volunteering needs if you would like to lend a hand in other ways.

Our Vision

Our Vision is for a Wales where adults and children with ME, CFS and PVFS and their carers are taken seriously and treated with respect, where diagnosis, treatment and services are accessible without a battle.

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Welsh Government responds & asks if NICE is being implemented

Posted on 03/21/2022 by wames

Welsh Government replies to WAMES

 

WAMES wrote to the Health Minister on 8 February asking why an announcement had been made about services for recent patients with long COVID, but not about services for people who have been living with ME for decades and…

how the Welsh Government will be funding and supporting a better understanding of ME/CFS, PESE/PEM and the dangers of exercise therapy, alongside the wider range of support needed for those with post COVID symptoms. We are looking for a speedy implementation of the 2021 NICE guideline.

#ImplementNICEmecfs

The Health Minister delegated her reply (again)

A civil servant from the ‘Government and Corporate Business Team’ wrote to update us on their work on ME/CFS and to ask us about recent patient experiences within NHS Wales:

During the winter each health board was surveyed in relation to their services for ME/CFS as well as their response to the revised NICE guidance. We have received assurances that
the new NICE guidance is being adopted. If your organisation has any evidence to the contrary we would welcome hearing about this. Within the survey we also queried what support is required to help improve services for all those presenting post viral symptoms and additional funding and training was mentioned.

What is your experience?

Are health professionals implementing the new NICE guideline?

Give us your experiences in any way you wish: email any of the team including jan@wames.org.uk or phone, email, comment on social media or this post.

The Welsh Government has assured us:

We agree there is much to learn from those with other post viral illnesses, including those with ME/CFS and can reassure you that ME/CFS is discussed at the vast majority of meetings considering long covid provision. Clinicians treating those with long Covid have advised of the similarities and there is a desire to ensure all services are suitable for all those living with the conditions.

As well as surveying health boards they are:

appointing a new senior policy lead whose remit will include long Covid, post viral conditions and ME/CFS. They will be tasked with working with stakeholders to deliver equity of outcome for all those needing support and we will ensure your comments are shared with them once they take up post.

Summing up, the Welsh Gov says:

  • There is much to learn about Long COVID from other post viral illnesses
  • ME/CFS is discussed at the vast majority of meetings considering long COVID provision
  • Clinicians have advised of the similarities between long COVID & ME/CFS
  • there is a desire in the NHS to ensure all services are suitable for all related conditions
  • Welsh Government is in the final stages of appointing a new senior policy lead whose remit will include long COVID, post viral conditions and ME/CFS
  • The aim is equity of outcome for all those needing support with post viral conditions
  • NHS Wales Health Boards say they are implementing new NICE guideline but need additional funding and training
  • Welsh Gov would welcome any evidence that the NICE guideline is not being implemented
  • Welsh Gov continues to explore how to expand integrated services for all people
    with post-viral illnesses and other long-term conditions, including ME/CFS.

Read the full letter

Read WAMES’ email to the Health Minister

Blog post: Wales prioritises healthcare for post-viral condition Long COVID

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Perspective: Drawing on findings from critical illness to explain ME/CFS

Posted on 03/16/2022 by wames

Perspective: Drawing on findings from critical illness to explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Dominic Stanculescu and  Jonas Bergquist in Front. Med., 08 March 2022 [doi.org/10.3389/fmed.2022.818728]

 

Abstract:

We propose an initial explanation for how myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) could originate and perpetuate by drawing on findings from critical illness research.

Specifically, we combine emerging findings regarding

(a) hypoperfusion [a reduced amount of blood flow] and endotheliopathy [damage to endothelial cells in the blood vessels] and

(b) intestinal injury in these illnesses with our previously published hypothesis about the role of

(c) pituitary suppression, [pituitary gland does not produce normal amounts of some or all of its hormones] and

(d) low thyroid hormone function associated with redox imbalance in ME/CFS.

Moreover, we describe interlinkages between these pathophysiological mechanisms as well as “vicious cycles” involving cytokines and inflammation that may contribute to explain the chronic nature of these illnesses. This paper summarizes and expands on our previous publications about the relevance of findings from critical illness for ME/CFS.

New knowledge on diagnostics, prognostics and treatment strategies could be gained through active collaboration between critical illness and ME/CFS researchers, which could lead to improved outcomes for both conditions.

Discussion
Hypoperfusion and endotheliopathy, intestinal injury, pituitary suppression, and low thyroid hormone function are each central to prolonged critical illness regardless of the nature of the initial severe injury or infection (101, 173, 195, 196).  We propose that, similarly, these mechanisms and their reciprocal relationships with inflammation could underlie ME/CFS regardless of the nature of the peri-onset event (i.e., infection, stressful incident, exposure to environmental toxins or other). Moreover, the severity of ME/CFS may be a function of the strength of these mechanisms.

However, each of these pathological mechanisms has largely been studied in isolation and rarely have the linkages between them been explored. Yet, the aggregate of these mechanisms is likely necessary to fully explain the perpetuation of critical illness—and to inform the understanding of ME/CFS.

Conclusion
Decades of research in the field of critical illness medicine have demonstrated that in response to the stress of severe infection or injury, the vascular system, intestines, endocrine axes and thyroid hormone function experience profound alterations. Self-reinforcing interlinkages between these pathophysiological mechanisms as well as “vicious cycles” involving cytokines and inflammation may perpetuate illness irrespective of the initial severe infection or injury.

Without excluding possible predisposing genetic or environmental factors, we propose that the pathological mechanisms—and the interlinkages between them—that prevent recovery of some critically ill patients may also underlie ME/CFS.

This initial proposal is in line with and complements several existing hypotheses of ME/CFS pathogenesis. If this hypothesis is validated, past treatment trials for critical illness may provide avenues for a cure for ME/CFS. Certainly, given the similarities described above, active collaboration between critical illness and ME/CFS researchers could lead to improved understanding of not only both conditions, but also PICS, long-COVID, PACS, and fibromyalgia.

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Research: Predictors for developing severe ME/CFS following infectious Mononucleosis

Posted on 03/14/2022 by wames

Predictors for developing severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following infectious Mononucleosis, by Leonard A Jason, Joseph Cotler, Mohammed F Islam, Jacob Furst, Ben Z Katz in Journal of Rehabilitation Therapy, 2022;4(1):1-5, February 21, 2022

 

Research abstract:

Background:

About 10% of individuals who contract infectious mononucleosis (IM) [aka Glandular fever] have symptoms 6 months later that meet criteria for myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS).  Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM.

Methods:

We have reported on a prospectively recruited cohort of 4,501 college students, of which 238 (5.3%) developed IM.  Those who developed IM were followed-up at six months to determine whether they recovered or met criteria for ME/CFS. The present study focuses on 48 students who after six months had a diagnosis of ME/CFS, and a matched control group of 58 students who had no further symptoms after their IM.

All of these 106 students  had data at baseline (at least 6 weeks prior to the development of IM), when experiencing IM, and 6 months following IM. Of those who did not recover from IM, there were two groups: 30 were classified as ME/CFS and 18 were classified as severe ME/CFS.

We measured the results of 7 questionnaires, physical examination findings, the severity of mononucleosis and cytokine analyses at baseline (pre-illness) and at the time of IM.  We examined predictors (e.g., pre-illness variables as well as variables at onset of IM) of  those who developed ME/CFS and severe ME/CFS following IM.

Results:

From analyses using receiver operating characteristic statistics, the students who had had severe gastrointestinal symptoms of stomach pain, bloating, and an irritable bowel at baseline  and who also had abnormally low levels of the immune markers IL-13 and/or IL-5 at baseline, as well as severe gastrointestinal symptoms when then contracted IM,  were found to have a nearly 80% chance of having severe ME/CFS persisting six months following IM.

Conclusions:

Our findings are consistent with emerging literature that gastrointestinal distress and autonomic symptoms, along with several immune markers, may be implicated in the development of severe ME/CFS.

Extract from Discussion:

The current study for the first time attempted to predict onset of ME/CFS using pre-illness and illness data. If validated, these predictors of risk could significantly alter the therapeutic strategies in IM and other triggers of ME/CFS in adults and adolescents. In addition, our work may lead to a reappraisal of the ME/CFS diagnostic criteria to include objective gastrointestinal and/or autonomic criteria for diagnosis.

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ME/CFS trigger: tuberculosis

Posted on 03/10/2022 by wames

Researchers have identified the mycobacterium tuberculosis infection as a trigger for CFS, particularly amongst men and the over 65s in Taiwan. TB in Wales is in decline and numbers are small, but the NHS considers it still to be a disease of concern. England has the highest rate of TB in the UK.

 

Tuberculosis (TB) is a bacterial infection spread through inhaling tiny droplets from the coughs or sneezes of an infected person. NHS Wales

 

How mycobacterium tuberculosis infection could lead to the increasing risks of chronic fatigue syndrome and the potential immunological effects: a population-based retrospective cohort study, by Tse-Yen Yang, Cheng-Li Lin, Wei-Cheng Yao, Chon-Fu Lio, Wen-Po Chiang, Kuan Lin, Chien-Feng Kuo & Shin-Yi Tsai in Journal of Translational Medicine vol 20, Article number: 99 (2022) [doi.org/10.1186/s12967-022-03301-1]

 

Research abstract: 

Background
Chronic fatigue syndrome (CFS) has been shown to be associated with infections. Tuberculosis (TB) is a highly prevalent infectious disease. Patients with chronic fatigue syndrome and post-tuberculosis experience similar symptoms.

Furthermore, chronic fatigue syndrome and tuberculosis share similar plasma immunosignatures. This study aimed to clarify the risk of chronic fatigue syndrome following the diagnosis of Mycobacterium tuberculosis infection (MTI), by analyzing the National Health Insurance Research Database of Taiwan.

Methods
7666 patients aged 20 years or older with newly diagnosed Mycobacterium tuberculosis infection during 2000–2011 and 30,663 participants without Mycobacterium tuberculosis infection were identified. Both groups were followed up until the diagnoses of chronic fatigue syndrome were made at the end of 2011.

Results
The relationship between Mycobacterium tuberculosis infection and the subsequent risk of chronic fatigue syndrome was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 3.04 and 3.69 per 1000 person‐years among the non‐Mycobacterium tuberculosis infection and Mycobacterium tuberculosis infection populations, respectively (adjusted hazard ratio [HR] = 1.23, with 95% confidence interval [CI] 1.03–1.47).

In the stratified analysis, the Mycobacterium tuberculosis infection group were consistently associated with a higher risk of chronic fatigue syndrome in the male sex (HR = 1.27, 95% CI 1.02–1.58) and age group of ≥ 65 years old (HR = 2.50, 95% CI 1.86–3.38).

Conclusions
The data from this population‐based retrospective cohort study revealed that Mycobacterium tuberculosis infection is associated with an elevated risk of subsequent chronic fatigue syndrome.

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Evaluating case diagnostic criteria for ME/CFS

Posted on 03/06/2022 by wames

Evaluating case diagnostic criteria for myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS): toward an empirical case definition, by Karl E Conroy, Mohammed F Islam, Leonard A Jason in Disability and Rehabilitation, Mar 2, p 1-8 2022 [doi.org/10.1080/09638288.2022.2043462]

 

Implications for rehabilitation

  • ME/CFS is a chronic illness with no consensus regarding case diagnostic criteria, which creates difficulty for patients seeking assistance and disability benefits.
  • The current study compared three commonly used case definitions for ME/CFS by factor analyzing symptomological data from an international sample of patients.
  • Our results suggest three primary and four secondary symptom domains which differed from all three case definitions.
  • These findings could help reduce barriers to care for those disabled with ME/CFS by guiding the development of an empirically-based case definition.

Abstract:

Purpose

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a variety of symptoms including post-exertional malaise, unrefreshing sleep, and cognitive impairment. A variety of case definitions (e.g., the Canadian Consensus Criteria (CCC), the Myalgic Encephalomyelitis International Consensus Criteria (ME-ICC), and the Institute of Medicine (IOM) criteria) have been used to diagnose patients. However, these case definitions are consensus-based rather than empirical.

Materials and methods

The aim of the current study was to evaluate the validity of the aforementioned case definitions by factor analyzing a large, international sample (N = 2308) of ME/CFS symptom data. We performed primary and secondary exploratory factor analyses on the DePaul Symptom Questionnaire‘s 54-item symptom inventory. These results were compared to the CCC, the ME-ICC, and the IOM criteria.

Results

We identified seven symptom domains, including post-exertional malaise, cognitive dysfunction, and sleep dysfunction. Contrary to many existing case criteria, our analyses did not identify pain as an independent factor.

Conclusions

Although our results implicate a factor solution that best supports the CCC, revisions to the criteria are recommended.

Full paper behind paywall

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Research: POTS found in long-haul COVID-19 patients: similarities with ME/CFS

Posted on 03/03/2022 by wames

Orthostatic symptoms and reductions in cerebral blood flow in long-haul COVID-19 patients: similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by  C (Linda) MC van Campen, Peter C Rowe and Frans C Visser in Medicina 2022, 58(1), 28 [doi.org/10.3390/medicina58010028]  24 December 2021
(This article belongs to the Special Issue Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms)

 

Research abstract:

Background and Objectives:

Symptoms and hemodynamic findings during orthostatic stress have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but little work has directly compared patients from these two groups. To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls.

Materials and Methods:

We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress.

Results:

There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response.

Conclusions:

The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS.

The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.

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Research review: Unknown aetiology: The case of ME/CFS and beyond

Posted on 03/02/2022 by wames

Current insights into complex Post-infection Fatigue Syndromes with unknown Aetiology: The case of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and beyond, by Francisco Westermeier, Eliana Mattos Lacerda,  Carmen Scheibenbogen and  Nuno Sepúlveda in Front. Med., 24 February 2022 [doi.org/10.3389/fmed.2022.862953]

 

Excerpts from journal editorial:

With the WHO notification of the COVID-19 as a pandemic on March 11, 2020, our third and final objective was to debate for the first time about ME/CFS as a sequela of post-SARS-CoV-2 infections. The graphical summary of all the contributions received is shown in Figure 1.

Old and new viral triggers for ME/CFS:

  • herpesviruses
  • enteroviruses
  • Ross River virus, which is an arbovirus endemic to Australia, Papua New Guinea, and other islands in the South Pacific
  • herpesviruses in patients from the United Kingdom ME/CFS biobank
  • SARS-CoV and SARS-CoV-2

Other studies published elsewhere provide further evidence that some long-COVID patients suffer from ME/CFS and, as such, there is a window of opportunity to improve the understanding of both conditions.

New perspectives on disease pathology and treatment

  • the same “vicious circle” between inflammation, oxidative and nitrosative stress, and low thyroid hormone function is operating in both some ME/CFS and patients in an intensive care unit (ICU)
  • pre-disease and early disease call for rehabilitation strategies that could avoid long-term co-morbidity while the management of the established disease should be more holistic and tailored to the specific needs of each patient
  • vascular abnormalities in ME/CFS – endothelial dysfunction
  • endothelial dysfunction and inadequate regulation of blood flow resulting in hypoperfusion of the brain and muscles
  • autoantibodies directed against vasoregulatory receptors contribute to the vascular dysregulation in ME/CFS
  • target autoreactive B cells or autoantibodies
  • the use of drugs that help regulating vascular function is another possibility to treat patients with ME/CFS.

Conclusions
In conclusion, this Research Topic collects further pieces of evidence about how various viruses including SARS-CoV-2 can trigger ME/CFS. The neglect of research in ME/CFS during the last decades has left patients, carers, and clinicians alike adrift without a licensed drug to use in the disease.

On the one hand, the COVID-19 pandemic will result in an unprecedented explosion of ME/CFS cases. At the same time, this pandemic is the perfect storm that can motivate different stakeholders, including funders and clinicians, to take the necessary steps to accelerate research on ME/CFS and other post-infectious syndromes. If taken, these steps will bring hope to all those outstanding patients who have been homebound or even bedridden for many years but neglected by national health authorities.

Read the full editorial

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