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Research Digest 29/09/22

Welcome to the 88th Emerge Australia Research Digest, where you will find summaries of some of the latest research and information about ME/CFS, with links to the complete articles.

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Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Authors: Vernon SD, Funk S, Bateman L, Stoddard GJ, Hammer S, Sullivan K … Komaroff AL (Harvard Medical School, United States). 
Publication: Frontiers in Medicine 

Following acute COVID-19 infection, approximately 2-40% of patients are developing Long COVID, a condition commonly causing persistent fatigue, orthostatic intolerance (OI), cognitive impairment and disrupted sleep. Long COVID shares symptom similarities with other post-infectious syndromes, with more severe forms of Long COVID clinically similar to ME/CFS. Routine diagnostic laboratory tests are often unremarkable, however autonomic disturbances are frequently reported by both Long COVID and ME/CFS patients. This study sought to determine whether an office-based test, the NASA Lean Test (NLT), could objectively evidence OI and associated brain fog.

This study included 42 patients with Long COVID (who had persistent symptoms for more than three months after infection with COVID-19), 26 ME/CFS patients (Institute of Medicine criteria), and 20 healthy controls (HCs). Participants were studied before, during, immediately after, then 2- and 7-days following completion of the NLT. Haemodynamic changes were measured by heart rate and blood pressure monitoring, and cognitive changes evaluated via a smart phone based app.

The authors found that the NLT triggered a worsening of symptoms in both patient groups, but not HC, and the severity of all symptoms reported was significantly worse in both patient groups. Both patient groups demonstrated a marked and progressive narrowing in pulse pressure, and all three cognitive measures of reaction time worsened in these two groups immediately following the NLT compared to the HCs.

The authors conclude that the NLT is an easily performed orthostatic stress test that is able to be performed in an office setting and reveal different symptomatic, haemodynamic and cognitive abnormalities in both patients with Long COVID and ME/CFS compared to HCs. The authors propose that the NLT can provide objective confirmation of symptoms of OI and brain fog commonly reported by both patient groups, and that this test may facilitate earlier detection and treatment of OI.

Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci 

Authors: Hajdarevic R, Lande A, Mehlsen J, Rydland A, Sosa DD, Strand EB, … Viken MK (Oslo University Hospital and University of Oslo, Norway) 
Publication: Brain, Behavior, and Immunity 

Previous studies searching for genetic risk factors linked to ME/CFS, particularly in genes linked to the immune system, have had inconsistent results. The authors believe this is because previous studies have been limited by small sample sizes and broad diagnostic criteria. The aim of this study was to undertake a genome-wide association study (GWAS) with three patient cohorts: a discovery cohort and two independent replication cohorts.  

The discovery cohort was Norwegian, consisting of 427 patients (Canadian Consensus Criteria or International Consensus Criteria) and 972 controls. The two independent replication cohorts were Danish and British. The Danish cohort consisted of 460 patients (Canadian Consensus Criteria) and 1965 controls, and the British cohort consisted of 2105 patients and 4786 controls.  

The authors found no replication of previously reported associations with the PTPN22 and CTLA4 genes (previously reported in patients who developed ME/CFS triggered by infection). Instead, they found the most significant loci associated with chromosomes 5, 10, 12, and 13 among the genes TPPP, IZUMO1/FUT1, ZBTB46, LINC00333, IGFBP1/IGFBP3, and RIN3. However, none of the SNPs identified, either through previous immunochip studies or through the authors examination of all single nucleotide polymorphisms (SNPs) in implicated regions, showed small enough p-values for genome-wide statistical significance to definitively conclude a genetic predisposition to ME/CFS.  

It is suggested that future studies use cohorts containing several thousand ME/CFS patients, preferably more homogenous in identification criteria and sub-phenotypes, for greater statistical power. The authors recommend further investigation into the above-mentioned regions warrant to firmly establish risk loci.

Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in Australian primary care patients: only part of the story? 

Authors: Orji N, Campbell JA, Wills K, Hensher M, Palmer AJ, Rogerson M, … de Graaff B (University of Tasmania, Australia) 
Publication: BMC Public Health 

The broad array of symptoms and limited understanding of the aetiology of ME/CFS have contributed to the development of more than 20 diagnostic criteria for the condition. The diversity of diagnostic criteria has in turn resulted in a lack of robust and comparable data for the prevalence of the condition. The aim of the present study was to investigate the prevalence of ME/CFS in Australian primary care settings. 

The study used primary care data in Australia-wide records from general medical practices. Extracted data covered the dates between 1 January 2014 to 31 December 2019, sourced from the MedicineInsight database. The authors also worked with a 20 member patient advisory group, to ensure that patient voices and insights guided the study. Nineteen participants with ME/CFS were recruited to participate in focus groups and in-depth 1:1 interview.  

The authors estimated the prevalence of ME/CFS in the Australian general practice setting between 2015 and 2019 to range between 94.9/100,000 and 103.9/100,000 populations (0.094%—0.14%), equating to approximately between 20,140 and 22,050 people with ME/CFS across Australia in 2020. Based on feedback from the patient advisory group, the authors noted that these are likely to be underestimates, as many ME/CFS patients do not attend GP clinics regularly due to lack of treatments and stigma. This feedback was supported by the qualitative evidence which identified barriers to reaching diagnosis leading to prolonged times to diagnosis, along with a lack of available treatments and stigma. 

The authors suggested more accurate prevalence rates could be calculated in future studies that use robust diagnostic criteria for case ascertainment in a community setting, and that accurate quantification of the burden of disease associated with ME/CFS should be used to inform health policy and plan and prioritise research funding for the condition.

Understanding myalgic encephalomyelitis 

Authors: Marshall-Gradisnik S, Eaton-Fitch N (Griffith University, Australia)  
Publication: Science 

A significant portion of people with ME/CFS have a post-infectious onset, and there is considerable overlap with post-infectious conditions like Long COVID. This article outlines the physiological dysfunctions identified in both ME/CFS and Long COVID. In particular, the article highlights the neurological, immune, calcium signalling, gastrointestinal and metabolic issues in both conditions. 

The authors highlight the lack of effective treatments available for ME/CFS, due in part to the difficulty identifying the underlying pathomechanism, as well as inconsistent findings in clinical trials due to small sample sizes, use of overly broad diagnostic criteria for participant selection and other confounding variables.  

The authors recommend the need for interdisciplinary research and consistent research protocols in order to progress understanding of ME/CFS and Long COVID.

Figure: Proposed mechanisms underlying ME/CFS

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