Key points
- History of ME/CFS – Dr Susan Levine acknowledged the extensive history of infectious outbreaks associated with ME/CFS, whilst highlighting five well-documented outbreaks: Los Angeles (1934), Akureyri (1948), the Royal Free Hospital (1955), Punta Gorda (1956), and Lake Tahoe (1984). Descriptions of symptoms arising from past infectious outbreaks align with certain core features of ME/CFS that we see nowadays, nevertheless individual outbreaks often had unique features such as distinctive laboratory findings. Several speakers discussed how ME/CFS cases have risen as a result of the COVID-19 (SARS CoV-2) pandemic.
- Clinical Assessment of ME/CFS and long COVID – Dr Lucinda Bateman highlighted her practical approach to managing patients with ME/CFS and long COVID. ” This approach involves treating all identifiable conditions and symptomatic aspects of the illness and encouraging “pacing” to prevent and reduce severity/duration of post-exertional malaise (PEM). Dr Bateman specifically highlighted the management of two common comorbidities: orthostatic intolerance and mast cell activation syndrome (MCAS).
- Biological abnormalities – Several potential biological abnormalities in ME/CFS and long COVID were discussed including the possibility of persistent antigens leading to immune exhaustion; disturbances of metabolism; and autoantibody levels linked to the severity of symptoms.
History of ME/CFS
Medical doctor and research fellow, Dr Susan Levine, set the tone for the conference with an overview of the history of ME/CFS following various infectious outbreaks. She mentioned that the majority of ME/CFS cases are thought to be due to an acute viral illness but in a minority of cases hormonal dysregulation may cause ME/CFS onset, e.g., postpartum, or following treatment for Grave’s disease.
Similarities between infectious outbreaks
Whilst acknowledging the vast history of infectious outbreaks associated with ME/CFS, Dr Levine focussed on five outbreaks: Los Angeles – US (1934), Akureyri – Iceland (1948), the Royal Free Hospital – London, UK (1955), Punta Gorda – Florida, US (1956), Lake Tahoe – Nevada, US (1984). Highlighting descriptions of symptoms from the Los Angeles outbreak resembling fatigue, post-exertional malaise (PEM), and neurological issues, she stated that “some of the descriptions of these earlier pandemics are remarkably similar to what we see today”. Following up decades after the Royal Free Hospital outbreak, Dr Melvin Ramsay and others noted that there were typically three groups of patients: individuals who in some cases recovered, individuals who did not recover at all, and those who had a relapsing-remitting pattern of illness. This mirrors what we see nowadays following infectious outbreaks. Furthermore, similar sequelae/comorbidities from previous outbreaks were noted, e.g. irritable bowel syndrome, and descriptions suggesting orthostatic intolerance/postural orthostatic tachycardia syndrome (POTS). Additionally, female predominance has been consistently noted.
Unique features of infectious outbreaks
In comparison to present day, Dr Levine noted that during the Punta Gorda outbreak, a wider range of neurological symptoms, such as fasciculations (muscle twitches) and photophobia, were frequently reported. The Royal Free Hospital outbreak, which affected medical staff more than patients, was characterised by nausea and vertigo, in addition to “serious upper respiratory, gastrointestinal, fatiguing, neurological” symptoms. “They had to close the hospital down because there literally wasn’t enough staff to take care of the patients.” Many of the patients from this outbreak demonstrated “cardiovascular, endocrine, and central nervous system sequelae”.
The Punta Gorda and Akureyri outbreak had unique laboratory findings of atypical lymphocytes (abnormal white blood cells), glucose imbalance, and EMG (neuromuscular test) abnormalities. The term “benign meningeal encephalomyelitis” was used to classify the Akureyri outbreak, however “[Dr] Melvin Ramsay … really objected to the description ‘benign’, and he said this isn’t benign, this is a really debilitating illness.” More laboratory testing was available by the time of the Lake Tahoe outbreak in which elevated EBV [Epstein-Barr virus] titres and abnormal T-cell ratios were noted, “unfortunately the CDC… did not investigate as thoroughly as was hoped.” Dr Levine described other unique features of certain infectious outbreaks, such as abnormal plantar responses (indicator of central nervous system dysfunction). One explanation she proposed in relation to the often lack of physical findings in ME/CFS nowadays, is that patients are typically seen several years into their illness, rather than in the acute stages.
How is this related to long COVID?
Dr Levine stated that the only silver lining to long COVID is that it “brings us an opportunity to study the immediate sequelae of a serious viral illness.” She believes that the “natural history is going to be similar to what has been described in previous epidemics – you are going to have people who recover completely, and others that … have more of a relapsing-remitting course, and some people who don’t get better at all”.
Like other infectious outbreaks, the COVID-19 (SARS CoV-2) pandemic has many shared features with other outbreaks, and additionally unique features, namely the “potential for organ involvement in long COVID” primarily related to the heart and lungs (although not all individuals report cardiorespiratory issues). Expert in computational genomics, Dr Wenzhong Xiao, displayed a graph during his talk with the incidence of the 20 most troubling symptoms reported by individuals with long COVID vs those with a diagnosis of ME/CFS, and overall, there were many similarities in relation to symptoms. Whilst a greater percentage of individuals with long COVID mentioned cardiorespiratory symptoms, specifically chest pain and shortness of breath, the top four most troubling symptoms reported for both groups were – fatigue/low energy, post-exertional malaise (PEM), “brain fog” (cognitive dysfunction) and unrefreshing sleep. According to NICE 2021 guidelines, these are the four symptoms needed for an ME/CFS diagnosis, hence it is no surprise that there are individuals with long COVID who either meet ME/CFS diagnostic criteria or have a concurrent ME/CFS diagnosis.
Clinical assessment of ME/CFS and long COVID
Diagnosis
Dr Lucinda Bateman, clinician, and medical director at the Bateman Horne Center, stated that “we know historically that ME/CFS specifically can be triggered by a variety of pathogens”. Within her presentation she included the family of coronaviruses (SARS CoV-1, MERS, SARS CoV-2) as associated with ME/CFS onset, alongside other viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), and non-viral agents such as giardia (a type of parasite). She also noted there are two main groups of individuals with long COVID: 1) “People who had severe infection, hospitalisation, post-ICU syndrome and/or lingering organ damage usually with objective markers” 2) “People with mild to moderate infection but lack of recovery, or even increasingly worse symptoms and impairment, yet without apparent biological markers”
These observations tie in with Dr Levine’s and Dr Xiao’s individual talks which draw attention to the similarities of symptoms between infectious outbreaks, alongside unique features such as the potential for organ involvement following a SARS CoV-2 infection.
“We know that people with ME/CFS, although it is a heterogenous condition, share the same core or common symptoms.” Dr Bateman highlighted that the U.S. National Academy of Medicine (NAM) ME/CFS 2015 criteria require the following features for an ME/CFS diagnosis:
- Impairment of normal function, accompanied by fatigue, persisting >6 months
- Post exertional malaise*
- Unrefreshing sleep*
- Cognitive impairment* and/or orthostatic intolerance
*Must be moderate-severe and frequent (present >50% of time)
In contrast to the NICE ME/CFS criteria, the NAM ME/CFS criteria not only includes orthostatic intolerance as a core symptom, but this symptom can be present instead of cognitive impairment. One study demonstrated that cognitive impairment frequently co-occurs with orthostatic intolerance, whereby 93.4% of ME/CFS participants reported both neurocognitive impairment and orthostatic intolerance.
Dr Bateman emphasised that ME/CFS is distinguished from other post-viral syndromes “by the amount of impairment or debilitation, and the development of post-exertional malaise.” She further stated, “in my opinion, and the opinion of most people who study post-viral syndromes and ME/CFS, if the symptoms in long COVID persisted 6 months and meet established criteria, you should make a diagnosis of ME/CFS, it can be post-COVID or post-SARS ME/CFS.”
“A time-tested practical treatment approach”
As “a clinician who has taken care of ME/CFS patients for a few decades” and gained insights from seeing long COVID patients in recent years, Dr Bateman shared her practical management approach. Her “formula” involves identifying and treating all identifiable conditions (co-morbid or separate) and encouraging “pacing” to prevent and reduce severity/duration of PEM. She further encouraged that major symptomatic aspects of the illness should be addressed such as sleep, pain and “mental wellness” (reduce grief/despair/discouragement/anxiety…).
She expanded upon the diagnosis and management of two common comorbidities: orthostatic intolerance (a major component of postural orthostatic tachycardia syndrome (POTS)) and mast cell activation syndrome (MCAS).
- Orthostatic intolerance – “development of symptoms in upright posture that are relieved or improved by reclining”
Orthostatic intolerance, identified with a passive or active stand test, can be managed through recognising and avoiding common exacerbating factors such as getting overheated, increasing blood volume, e.g. increasing water and salt intake, external compression of blood vessels e.g. wearing compression socks, and various pharmacological interventions with mechanisms such as controlling heart rate response and constricting blood vessels.
- MCAS – activation of mast cells (a type of white blood cell that releases inflammatory chemicals such as histamine)
Symptoms of MCAS are episodic and affect many body systems, including – but not limited to – skin (urticaria/hives), gastrointestinal (nausea and vomiting), cardiorespiratory (fainting, wheezing). MCAS symptoms should improve with pharmacological interventions (largely targeted at stabilising mast cells and blocking the effects of histamine and other inflammatory mediators). Dr Bateman emphasised that “when there is a clinical suspicion for MCAS, successful trials of MCAS therapy strengthen the diagnosis, even if markers are elusive.”
Dr Bateman discussed “ a simple tool to communicate impaired function” in relation to Hours of “Upright” Activity (HUA). HUA refers to the total number of hours spent with “feet-on-floor” in 24 hours (sitting, standing, walking). The estimate ranges for HUA for people with ME/CFS /orthostatic intolerance/POTS were much lower than healthy individuals, which correlates with greater impairment in functioning on a day-to-day basis.
Aligning with Dr Bateman’s talk, medical doctor – Dr Luis Nacul, highlighted a succinct approach to ME/CFS patients: “Assess, diagnose, legitimise, address needs, support, treat”. Furthermore, the importance of establishing a partnership with patients and working as part of a multi-disciplinary team was underscored.
Biological abnormalities: Immune system and metabolism
Following on from the biological abnormalities discussed in Part 1 of our conference coverage, immune and metabolic abnormalities in ME/CFS and long COVID were also described. Highlights include:
- Persistent antigenic stimulation – Dr Maureen Hanson, professor in Molecular Biology and Genetics, examined the evidence for persistent antigens in ME/CFS and long COVID, i.e., foreign agents that remain in the body for an extended period, continuously stimulating the immune system. Persistent antigen stimulation may lead to “exhaustion” of the immune system. Dr Hanson highlighted several abnormalities found in relation to T-cells (white blood cells essential for immune response) which suggest this phenomenon.
- Disturbed metabolism – Clinical immunologist and researcher at Charité University in Berlin, Professor Carmen Scheibenbogen, discussed a Charité study which found potential markers for endothelial inflammation and metabolic disturbances in post-COVID ME/CFS. Likewise, Professor in Analytical Chemistry and Neurochemistry, Dr Jonas Bergquist, and his research team have been analysing hundreds of metabolites (products of metabolism) and have noted many abnormalities suggestive of a disturbed metabolism in ME/CFS.
- Autoimmunity –Referencing multiple research papers, Professor Scheibenbogen stated that there is much evidence of autoimmunity (immune system mistakenly attacking its own tissues) in ME/CFS. She further highlighted evidence of autoantibodies against G-protein couple receptors whereby level of autoantibodies correlated with symptom severity. Professor Scheibenbogen’s team conducted clinical trials involving immunoadsorption – technique of removing autoantibodies from the blood – which led to symptom improvement (for differing time periods) in many patients with ME/CFS and post-COVID ME/CFS.
Conclusion
The 1st International Conference on Clinical and Scientific Advances in ME/CFS and Long COVID in Lisbon provided a comprehensive overview of the history, clinical assessment, and biological abnormalities associated with these conditions. Through insights shared by many experts, parallels were drawn between past infectious outbreaks and the COVID-19 pandemic, both shedding light on shared symptoms and highlighting distinctive features.
Read Part 1 of ME Research UK’s Lisbon Conference Highlights.
Watch individual presentations.
