Sex-based differences in plasma autoantibodies to CNS proteins in Gulf War veterans versus healthy & symptomatic controls

Posted on 02/22/2021 by wames

Sex-based differences in plasma autoantibodies to Central Nervous System proteins in Gulf War veterans versus healthy and symptomatic controls, by Mohamed B Abou-Donia, Maxine H Krengel, Elizabeth S Lapadula, Clara G Zundel, Jessica LeClair, Joseph Massaro, Emily Quinn, Lisa A Conboy, Efi Kokkotou, Daniel D Nguyen, Maria Abreu, Nancy G Klimas, Kimberly Sullivan in Brain Sci. 2021 Jan 23;11(2):148 [doi: 10.3390/brainsci11020148] (This article belongs to the Special Issue Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness)

 

Research abstract

Veterans from the 1991 Gulf War (GW) have suffered from Gulf War illness (GWI) for nearly 30 years. This illness encompasses multiple body systems, including the central nervous system (CNS). Diagnosis and treatment of GWI is difficult because there has not been an objective diagnostic biomarker. Recently, we reported on a newly developed blood biomarker that discriminates GWI from GW healthy controls, and symptomatic controls with irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

The present study was designed to compare levels of these biomarkers between men and women with GWI, as well as sex-specific effects in comparison to healthy GW veterans and symptomatic controls (IBS, ME/CFS). The results showed that men and women with GWI differ in 2 of 10 plasma autoantibodies, with men showing significantly elevated levels. Men and women with GWI showed significantly different levels of autoantibodies in 8 of 10 biomarkers to neuronal and glial proteins in plasma relative to controls.

In summary, the present study addressed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among both men and women veterans with GWI and other healthy and symptomatic control groups.

Excerpt

Our next analyses compared male veterans with GWI to all male controls from our prior study (healthy GW veterans, non-veterans with IBS or ME/CFS) [19]. We then performed the same analyses comparing women veterans with GWI to the combined all women control group (non-veterans with IBS and ME/CFS). The results showed that men with GWI had significantly higher levels of autoantibodies for 9 out of the 10 autoantibodies when compared with male healthy GW veterans or with the combined male control group. Women with GWI showed significantly higher values for 2 out of the 10 autoantibodies when compared with women healthy GW veterans and with 8 out of 10 autoantibodies when compared with their respective combined women control group (nonveterans with IBS and ME/CFS).

These results suggest that women with GWI appear to be showing more neuronal cytoskeletal and neuroinflammatory changes when compared to healthy GW controls or women with IBS or ME/CFS

This suggests that male GWI veterans may be showing more chronic glial activation, neuronal damage, and neuroinflammation than their male control healthy and symptomatic counterparts with IBS and ME/CFS because S100B is a marker of current BBB disruption and GFAP is a marker of current neuroinflammation [39,40]. This is because GFAP is secreted by activated astrocytes, which leads to neuroinflammation [41,42,43].

A major strength of our study is that it represents both healthy and symptomatic GW veteran groups as well as symptomatic non-veteran controls with ME/CFS or IBS. This suggests that both men and women veterans with GWI differ not only from their healthy GW veteran controls but also have more CNS differences than other groups of men and women with chronic multi-symptom illnesses. In addition, the CNS autoantibody analyses were performed with the laboratory staff blinded to the case status of all participants.

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Sick of the sick role: narratives of what ‘recovery’ means to people with CFS/ME

Posted on 02/21/2021 by wames

Sick of the sick role: narratives of what “Recovery” means to people with CFS/ME, by Anna Cheshire, Damien Ridge, Lucy V Clark, Peter D White in Qualitative Health Research Vol 31, Issue 2, 2021 [doi.org/10.1177/1049732320969395]

 

Research abstract:

Little is known about what recovery means to those with chronic fatigue syndrome/ myalgic encephalomyelitis, a poorly understood, disabling chronic health condition.

To explore this issue, semi-structured interviews were conducted with patients reporting improvement (n = 9) and deterioration (n = 10) after a guided self-help intervention, and analyzed via “constant comparison.”

The meaning of recovery differed between participants—expectations for improvement and deployment of the sick role (and associated stigma) were key influences. While some saw recovery as complete freedom from symptoms, many defined it as freedom from the “sick role,” with functionality prioritized. Others redefined recovery, reluctant to return to the lifestyle that may have contributed to their illness, or rejected the concept as unhelpful.

Recovery is not always about eliminating all symptoms. Rather, it is a nexus between the reality of limited opportunities for full recovery, yet a strong desire to leave the illness behind and regain a sense of “normality.”

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Plasma proteomics publication shows disrupted cell-to-cell signaling in ME/CFS

Posted on 02/18/2021 by wames

Cornell University news post from the Center for Enervating NeuroImmune Disease: Plasma proteomics publication shows disrupted cell-to-cell signaling

 

We are proud to announce our latest plasma proteomics publication is available as open access in Proteomes.

In-depth analysis of the plasma proteome in ME/CFS exposes disrupted Ephrin-Eph and immune system signaling by Arnaud Germain, Susan M Levine and Maureen R Hanson in Proteomes 2021, 9(1), 6; [doi.org/10.3390/proteomes9010006]

This manuscript takes a look at 4,790 circulating plasma proteins from 20 ME/CFS women compared to 20 healthy women, over an unprecedented range, for ME/CFS, of 9 orders of magnitude.

Pathway analysis uncovered disrupted cell-to-cell communication, specifically in the ephrin-Eph signaling pathway. This pathway is crucial for many aspects of our body’s homeostasis, including development, physiology, and disease regulation.

Additionally, the paper outlines promising results for the development of a diagnostic test using protein ratios.

First author, Arnaud Germain, PhD, outlines these findings in a video abstract below (4 mins).

A transcript for the video: English        German

 

 

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Open‐label study with the monoamine stabilizer (‐)‐OSU6162 [drug] in ME/CFS

Posted on 02/18/2021 by wames

Open‐label study with the monoamine stabilizer (‐)‐OSU6162 in myalgic encephalomyelitis/ chronic fatigue syndrome, by Sara Haghighi, Sara Forsmark, Olof Zachrisson, Arvid Carlsson, Marie K L Nilsson, Maria L Carlsson, Robert C Schuit, Carl‐Gerhard Gottfries in Brain and Behavior, 02 February 2021 [doi.org/10.1002/brb3.2040]

 

Research abstract:

Objectives

The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (‐)‐OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (‐)‐OSU6162 in ME/CFS was evaluated by means of observer‐rated scales and self‐assessment rating scales.

Materials and Methods

In the current study using an open‐label single‐arm design ME/CFS patient received treatment with (‐)‐OSU6162 during 12 weeks. The patients received the following doses of (‐)‐OSU6162: 15 mg b.i.d. during the first 4‐week period, up to 30 mg b.i.d. during the second 4‐week period and up to 45 mg b.i.d. during the third 4‐week period, with follow‐up visits after 16 and 20 weeks.

Results

Out of 33 included patients, 28 completed the 12 weeks treatment period. (‐)‐OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire.

Conclusions

(‐)‐OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health‐related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo‐controlled double‐blind trials.

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Diagnostic & pharmacological potency of Creatine in Post-Viral Fatigue Syndrome

Posted on 02/18/2021 by wames

Diagnostic and pharmacological potency of creatine in Post-Viral Fatigue Syndrome
by  Sergej M. Ostojic in Nutrients 2021, 13(2), 503; [doi.org/10.3390/nu13020503] (This article belongs to the Special Issue Creatine Supplementation for Health and Clinical Diseases)

 

Review abstract

Post-viral fatigue syndrome (PVFS) is a widespread chronic neurological disease with no definite etiological factor(s), no actual diagnostic test, and no approved pharmacological treatment, therapy, or cure.

Among other features, PVFS could be accompanied by various irregularities in creatine metabolism, perturbing either tissue levels of creatine in the brain, the rates of phosphocreatine resynthesis in the skeletal muscle, or the concentrations of the enzyme creatine kinase in the blood. Furthermore, supplemental creatine and related guanidino compounds appear to impact both patient- and clinician-reported outcomes in syndromes and maladies with chronic fatigue.

This paper critically overviews the most common disturbances in creatine metabolism in various PVFS populations, summarizes human trials on dietary creatine and creatine analogs in the syndrome, and discusses new frontiers and open questions for using creatine in a post-COVID-19 world.

Conclusions

Currently, there is not enough evidence to unequivocally endorse supplemental creatine for PVFS. However, the findings from initial trials on the metabolic substrate of PVFS, along with promising results from interventional studies, emphasize the need to explore creatine and similar compounds in this ever-prevalent yet baffling disorder.

The need for an effective, low-risk, and affordable dietary intervention to tackle post-COVID-19 fatigue, which is going to remain an issue for years to come, perhaps provides a unique research opportunity to explore creatine in PVFS using expedited yet diligent approaches.

 

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Chronic COVID-19 Syndrome & ME/CFS following the first pandemic wave in Germany

Posted on 02/15/2021 by wames

Chronic COVID-19 Syndrome and Chronic Fatigue Syndrome (ME/CFS) following the first pandemic wave in Germany – a first analysis of a prospective observational study, n medRxiv 2021.02.06.21249256 [doi.org/10.1101/2021.02.06.21249256]  This article is a preprint and has not been peer-reviewed

 

Research abstract:

Objective:

Characterization of the clinical features of patients with persistent symptoms after mild to moderate COVID-19 infection and exploration of factors associated with the development of Chronic COVID-19 Syndrome (CCS).

Methods Setting:

Charité Fatigue Center with clinical immunologists and rheumatologist, neurologists and cardiologists at Charité University hospital.

Participants:

42 patients who presented with persistent moderate to severe fatigue six months following a mostly mild SARS-CoV-2 infection at the Charité Fatigue Center from July to November 2020.

Main outcome measures:

The primary outcomes were clinical and paraclinical data and meeting diagnostic criteria for Chronic Fatigue Syndrome (ME/CFS). Relevant neurological and cardiopulmonary morbidity was excluded.

Results: 

The median age was 36.5, range 22–62, 29 patients were female and 13 male. At six months post acute COVID-19 all patients had fatigue (Chalder Fatigue Score median 25 of 33, range 14–32), the most frequent other symptoms were post exertional malaise (n=41), cognitive symptoms (n=40), headache (n=38), and muscle pain (n=35). Most patients were moderately to severely impaired in daily life with a median Bell disability score of 50 (range 15–90) of 100 (healthy) and Short Form 36 (SF-36) physical function score of 63 (range 15-80) of 100. 19 of 42 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

These patients reported more fatigue in the Chalder Fatigue Score (p=0.006), more stress intolerance (p=0.042) and more frequent and longer post exertional malaise (PEM) (p=0.003), and hypersensitivity to noise (p=0.029), light (p=0.0143) and temperature (p=0.024) compared to patients not meeting ME/CFS criteria. Handgrip force was diminished in most patients compared to healthy control values, and lower in CCS/CFS compared to non-CFS CCS (Fmax1 p=0.085, Fmax2, p=0.050, Fmean1 p=0.043, Fmean2 p=0.034, mean of 10 repeat handgrips, 29 female patients). Mannose-binding lectin (MBL) deficiency was observed frequently (22% of all patients) and elevated IL-8 levels were found in 43% of patients.

Conclusions:

Chronic COVID-19 Syndrome at months 6 is a multisymptomatic frequently debilitating disease fulfilling diagnostic criteria of ME/CFS in about half of the patients in our study. Research in mechanisms and clinical trials are urgently needed.

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Long COVID – we’ve been here before

Posted on 02/15/2021 by wames

British Medical Association news:  Long COVID – we’ve been here before
by Jennifer Trueland, 12 February 2021

 

Long COVID is a new condition, but those who have endured years of ME/CFS can share their common experience – and a long history of being misunderstood

When it was becoming clear that COVID-19 was a serious issue early last year, Nina Muirhead (pictured) had a strong suspicion about what would happen next.

As a doctor who had developed ME/CFS following an attack of glandular fever four years ago, and in common with others in the scientific and ME patient community, she predicted that there would be a sub-set of people who, like her, would still be suffering months or even years after contracting the virus.

‘I wrote to Professor Whitty [England’s chief medical officer] and Sir Patrick Vallance [chief scientific officer] back in March saying there’s going to be a long COVID, and maybe there should be a health warning put out about this – maybe people should be advised of the long-term consequences, maybe we could do a study.

‘But they were so overwhelmed with fighting the big fire [acute COVID], and because ME is so misunderstood by the medical profession, they didn’t have the same end of the binoculars as I do. They didn’t see it coming in the same way.’

Nearly a year on, it’s becoming accepted that long COVID is a serious problem. The Office for National Statistics said in December that an estimated one in five people testing positive for COVID-19 exhibit symptoms for five weeks or longer, with one in 10 exhibiting symptoms for 12 weeks or longer…

Amy Small, a GP in Lothian who has campaigned on long COVID after becoming ill herself, acknowledges that she has learned a lot about management of the condition from the experience of people with ME/CFS.

‘One of the first things I did when I realised that I wasn’t getting better was that I phoned a friend who has had severe ME for several years.

‘I asked her what would you want to know if you were me now, and you could see this coming – what would you do? She suggested pacing first and foremost – learn to pace properly. I had never really understood what pacing was – I thought it was to do what you’re doing, but do it more slowly.

‘But someone on Twitter recommended a book to me called Classic Pacing for a Better Life with ME and that was a real turning point for me.’

h long COVID had found giving up sugar very helpful, and she’s got me on a load of supplements. I said to my husband years ago that if he ever caught me taking turmeric for medicinal purposes, then shoot me,’ she laughs. ‘Boy did I live to regret that. I think my attitude has changed.’

Keeping a symptom diary and consulting a nutritionist have also been helpful – although Dr Small admits that some of the advice would previously have been anathema to her as an evidence-focused medic.

Read more from Dr Nina Muirhead, Dr Charles Shepherd and Dr David Strain, an ME/CFS researcher, now leading the BMA’s COVID response.

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Young and exhausted – dysfunctional breathing

Posted on 02/14/2021 by wames

Young and exhausted, by Filip Olekšák, Peter Ďurdík, Ľubica Jakušová, Tomáš Turčan, Peter Bánovčin in Advances in Respiratory Medicine 2021, vol. 89, no. 1, pages 1-4

 

Letter to the editors extracts:

Dysfunctional breathing (DB) is highly prevalent and is overlooked mainly in adolescents and often attributed to behavioural changes during adolescence [6]. Chronic fatigue might be a symptom of DB in adolescents. We present a case study supporting this claim.

Case report

In the case report, we present a 13-year-old patient with chronic debilitating fatigue who
meets the criteria for CFS/ME. The patient and patient’s parents reported 6 months of fatigue, which was not improved even after an adequate period of sleep and very low physical performance. According to the parents, the patient has difficulty concentrating, is morose most of the day and reports limb twitching and paraesthesia.

The patient was examined in detail by a paediatrician (anamnestic unclear cause, resting tachycardia in the physical examination, laboratory tests within normal limits, serum minerals within normal limits), endocrinologist (normal hormonal profile for a given age, Tanner stage 3), infectologist (serology for typical viruses negative), psychologist (normal cognitive functions).

For a history of resting tachycardia, the patient was examined by a cardiologist, where no cardiogenic cause of fatigue was demonstrated, sinus tachycardia was present, and the patient was recommended head-up-tilt test, which showed the presence of postural orthostatic tachycardia. Due to the idiopathic nature of the difficulties and the excluded secondary cause, a two-day protocol examination by cardiopulmonary exercise testing was indicated.

Conclusions
CPET confirmed the presence of DB in the patient based on the low resting value of ETCO2, the existence of a chaotic pattern of respiration  during resting and exercise with the presence of tachypnoea (with very low ventilatory efficiency) in maximal exertion. Diagnosis of DB using CPET is one of the methods of DB diagnostics. Proper respiratory rehabilitation and psychological guidance resulted in the patient fixing the respiratory pattern and subsequently eliminating the primary cause of the examination — chronic fatigue.

Patients with CFS/ME are a common paediatric problem. The current possibilities of diagnostics are enriched by the possibility of performing CPET, which can be a benefit in differential diagnostics as well as in confirming the diagnosis. Patients with CFS/ME and/or postural orthostatic tachycardia should be checked for the presence of DB as a treatable cause of clinical symptoms.

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The challenges of chronic pain & fatigue [for clinicians]

Posted on 02/14/2021 by wames

The challenges of chronic pain and fatigue, by Jessica A Eccles and Kevin A Davies in Clin Med January 2021 [doi.org/10.7861/clinmed.2020-1009]

 

Review abstract:

In this review, we explore the challenges of chronic pain and fatigue in clinical practice. Both pain and fatigue are common, troubling and frequently overlapping symptoms, and we describe both the clinical burden and the ‘clinical problem’. We explore commonly associated symptoms and possible pathological associations, including variant connective tissue (joint hypermobility), small fibre neuropathy, mast cell activation, dysregulated inflammatory and interoceptive processes, which may inform treatment targets. We suggest a multidisciplinary management approach.

[The paper explores ME/CFS, Fibromyalgia, POTs, Long COVID, Mast Cell Activation, Small fibre neuropathy, Joint hypermobility, IBS]

Excerpt:

Outpatient assessment of a patient with fatigue and chronic pain can be challenging. This is particularly the case when the patient is polysymptomatic and they have had many interactions with healthcare professionals before. It is all too easy to ‘admit defeat’ as in Dr A’s case, or initiate a test or another referral in ‘response’ to every symptom described by the patient during the course of their illness (Dr B). How can this be avoided?

One approach is to adopt the ‘snapshot’ approach and ask the patient to identify a maximum of three ‘live’ clinical problems (eg in the previous 2 weeks), highlighting which is the most significant one. If the primary problem is fatigue or pain (as in our exemplar Patient A), it can be highly informative to identify the single most important additional symptom: the ‘plus one’ approach. This should raise a specific subset of diagnostic possibilities, often limited in number, which will prompt further, more focused ‘direct’ questioning, and may inform an initial investigation strategy, if considered appropriate.

All physicians are trained to identify ‘red flag’ symptoms, such as unexplained weight loss, which, in older patients particularly, may point to a diagnosis of malignancy, malabsorption, endocrine disease or depression. However, there is a number of conditions that are frequently missed, and easily identified. Some of these are summarised in Table 1. We focus on the ‘plus one’. The average time it takes to diagnose Behçet’s, for example, may be up to 7 years and there is frequently a delay in the diagnosis of Sjogren’s syndrome; few doctors ask about sicca.64 Inflammatory bowel disease or endometriosis can also easily be missed, as can HIV, especially in older patients.65,66.

What is rarely helpful or informative in a busy clinic setting is to rehearse in detail with a patient the detailed chronology of what may be several years of ill-health. This can all too often result in a ‘memory test’ for the patient, with the physician seeking to corroborate dates and details in the notes or electronic patient record. This wastes time, and can be frustrating for all concerned. However, it may be useful before, or more often after, the consultation to look back at previous letters, imaging or pathology results to help substantiate or refute a presumptive diagnosis.

In patients with a ‘long history’ and multiple medical interactions, it is, however, important to avoid ‘medical transference’ and give undue credence to diagnoses made by other doctors, often years before. Firstly, the patient’s recollection of the outcome of a previous consultation may be far from accurate, and secondly, the professor may well have been wrong. It does happen.

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Experiences of living with severe CFS/ME

Posted on 02/12/2021 by wames

Experiences of living with severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, by  Victoria Strassheim, Julia L Newton and Tracy Collins in Healthcare 2021, 9(2), 168 [doi.org/10.3390/healthcare9020168] (This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)

 

Research abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a rare disease with no known etiology. It affects 0.4% of the population, 25% of which experience the severe and very severe categories; these are defined as being wheelchair-, house-, and bed-bound. Currently, the absence of biomarkers necessitates a diagnosis by exclusion, which can create stigma around the illness.

Very little research has been conducted with the partly defined severe and very severe categories of CFS/ME. This is in part because the significant health burdens experienced by these people create difficulties engaging in research and healthcare provision as it is currently delivered.

This qualitative study explores the experiences of five individuals living with CFS/ME in its most severe form through semi-structured interviews. A six-phase themed analysis was performed using interview transcripts, which included identifying, analysing, and reporting patterns amongst the interviews. Inductive analysis was performed, coding the data without trying to fit it into a pre-existing framework or pre-conception, allowing the personal experiences of the five individuals to be expressed freely.

Overarching themes of ‘Lived Experience’, ‘Challenges to daily life’, and ‘Management of the condition’ were identified. These themes highlight factors that place people at greater risk of experiencing the more severe presentation of CFS/ME. It is hoped that these insights will allow research and clinical communities to engage more effectively with the severely affected CFS/ME population.

 

Conclusions

This study is novel, as it has accessed this hard to reach population group and recorded their experience. Most of the participants had received some form of specialist CFS/ME support or had access to the healthcare services. However, their experiences ranged from accepting the limitations of the service to having a very negative view.

CFS/ME is a medically unexplained illness lying at the boundaries of understanding within the legacy biomedical model. An illness where there is no single, simple cause or theoretical model, no clear mind/body division, and no definitive classification [1] does not sit easily in the current healthcare system. The CFS/ME presentation conflicts with the current health and social care model [1,2]. The severe CFS/ME presentation sits outside the model and therefore is not acknowledged.

This illness ranks low within primary care, as it is not life threatening [23]. However, it is potentially life shortening [14]. There are certainly physical and mental health symptoms that are often disregarded or missed within the complex presentation [14], and reports suggest that 88 suicides have been partly attributed to CFS/ME between 2001 and 2016. However, it has been noted that it is not necessarily intrinsic factors that lead to suicide, but a combination of extrinsic factors, which include a lack of medical care and social support, failure to control key symptoms, and inadequate financial help. Depression is not always a feature in CFS/ME-related suicide [49].

…Currently, the healthcare system and research community are failing to provide resources and opportunities for this group to engage, and so enable the positive outcome of increased independence. Longer periods of intervention, home visits and telephone consultations and in extreme cases inpatient rehabilitation in specialist services are effective evidenced interventions in the research literature [10,16,44,53]. Such services would meet the needs of CFS/ME individuals much better than the status quo which often forces patients to meet the needs of the system in order to secure the care that they need.

A re-evaluation of the approach taken to CFS/ME and other unexplained illness is ever more urgent given the upcoming surge in numbers of long-haul COVID-19 individuals. A major symptom of such long-haul COVID-19 is fatigue [54,55]. Research and healthcare communities have much experience to share and further research to perform, particularly in the area of health, social care, and societal attitudes allowing vulnerable ill people to remain valued members of society.

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