Community Advisory Committee Develops Priorities for ME/CFS Research

Press Release:

Posted by CII Coordinator, May 10, 2022

The Community Advisory Committee (CAC) for the NIH ME/CFS Research Network was established to bridge the gap between researchers and the ME/CFS community with the goal of accelerating the pace of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) research. The CAC is a group of 15 individuals from various professional backgrounds, all of whom have lived experience of the disease.

The CAC Research Priorities working group has authored a report on the challenges and priorities to be addressed to achieve needed outcomes for people with ME/CFS. This has become especially urgent given the large number of people who already have, and are expected to develop, ME/CFS following COVID-19.

ME/CFS is a debilitating, chronic, complex disease that most often follows an infection and is associated with neurological, autonomic, immunological, and metabolic abnormalities. Patients experience a substantial impairment in functioning, and symptoms such as sleep dysfunction, cognitive impairment, orthostatic intolerance, pain, fatigue, and the hallmark post-exertional malaise (PEM), an exacerbation of symptoms following even small amounts of previously tolerated activity. An estimated 836,000 to 2.5 million Americans suffer from ME/CFS with a greater prevalence in females, adults and possibly people who are Black and Latinx. There are no validated biomarkers or FDA-approved treatments and patients can struggle to access adequate clinical care. An estimated 25% are homebound or bedbound and 75% are unable to work. Recovery is rare and patients can remain ill for decades.

Progress in understanding the etiology of ME/CFS and developing biomarkers and treatments has been constrained by a number of interrelated challenges, such as the inherent complexity and heterogeneity of the disease, inadequate study methods, challenges in collaborating across all stakeholders, misunderstanding about the nature of the disease, and lack of research funding and researchers in the field. But even with these challenges, substantial progress has been made in understanding some of the underlying pathology.

The pandemic has created the tragic opportunity to finally understand how an infection can result in chronic illness. At the same time, the knowledge and expertise gained from years of ME/CFS research has provided valuable insights for Long COVID research.

Leveraging this opportunity for ME/CFS requires ME/CFS-specific funding and a ME/CFS strategic research plan to expedite progress in ME/CFS diagnostics and treatments. It also requires the integration of learnings from ME/CFS research into the PASC strategy, not only to help accelerate research in Long COVID but to better understand ME/CFS onset, natural history, and pathology. A natural experiment is underway which cannot be replicated, and this calls for swift, decisive action before the window of opportunity to study early-onset ME/CFS closes as the pandemic resolves.

People with ME/CFS, including those who have developed ME/CFS following COVID-19, are waiting.

The CAC Research Priorities working group developed this comprehensive but concise report outlining the long-standing barriers that have constrained progress in ME/CFS and strategies for their resolution, as well as key short and longer term research priorities that need to be progressed to accelerate meaningful research and achieve outcomes for people with ME/CFS, including those whose ME/CFS developed following COVID-19. These recommendations can be used by researchers to generate new study designs and refine existing goals, facilitate collaborations between research domains and stakeholders, and by federal and private funders to guide award distribution and agenda setting.

Click here to download the CAC Research Priorities Report

The Research Priorities working group is available and eager to discuss the contents of this document with researchers. Please contact us at any time at: CAC.MECFS@gmail.com

The authors of this guide are: Mary Dimmock, Rochelle Joslyn (chair), Sabrina Poirier, Jaime Seltzer and CAC Director, Allison Kanas.

This work was supported by US Public Health Service grant 5U54AI138370 and 5U24NS105535. This content does not represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.

Gastric herpes simplex virus type 1 infection is associated with functional gastrointestinal disorders in the presence and absence of comorbid fibromyalgia: a pilot case-control study

Abstract:

Purpose: Animal studies have linked gastric herpesvirus infections to symptoms associated with functional gastrointestinal disorders (FGIDs). Herpesviruses have also been hypothesized to contribute to fibromyalgia (FM), a chronic pain syndrome frequently comorbid with FGIDs. The purpose of this study was to compare the prevalence of gastric herpesvirus infection in patients with FGIDs, with and without comorbid FM, to that of controls.

Methods: For this pilot case-control study, we enrolled 30 patients who met both the Rome IV diagnostic criteria for one or more FGIDs and the American College of Rheumatology 2010 criteria for FM, 15 patients with one or more FGIDs without comorbid FM, and 15 control patients. Following endoscopic examination, gastric biopsies were analyzed for herpesvirus DNA and protein, Helicobacter pylori infection, and histological evidence of gastritis. Importantly, the viral nonstructural protein ICP8 was used as a marker to differentiate cell-associated actively replicating virus from latent infection and/or free virus passing through the GI tract.

Results: Gastric herpes simplex virus type 1 (HSV-1) infection, as indicated by ICP8 presence, was significantly associated with FGIDs in the presence (OR 70.00, 95% CI 7.42-660.50; P < .001) and absence (OR 38.50, 95% CI 3.75-395.40; P < .001) of comorbid FM. Neither histological gastritis nor H. pylori infection were found to be associated with FGIDs or FM.

Conclusions: HSV-1 infection was identified in gastric mucosal biopsies from patients with diverse FGIDs, with and without comorbid FM. Larger, multi-center studies investigating the prevalence of this association are warranted.

Source: Duffy C, Pridgen WL, Whitley RJ. Gastric herpes simplex virus type 1 infection is associated with functional gastrointestinal disorders in the presence and absence of comorbid fibromyalgia: a pilot case-control study. Infection. 2022 Apr 21. doi: 10.1007/s15010-022-01823-w. Epub ahead of print. PMID: 35445970.  https://link.springer.com/article/10.1007/s15010-022-01823-w (Full text)

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome

To the Editor:

After acute infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many individuals experience a range of symptoms including dyspnea, exercise intolerance, and chest pain commonly referred to as “post–COVID-19 syndrome” or as post-acute sequelae of SARS-CoV-2 infection (PASC) (). Exertional dyspnea and physical activity intolerance in PASC can be debilitating despite mild acute coronavirus disease (COVID-19) and normal resting pulmonary physiology and cardiac function (). There is an urgent need to understand the pathogenesis of PASC and find effective treatments. The cardiopulmonary exercise test (CPET) is commonly used to investigate unexplained exertional dyspnea; as such, it could provide insight into mechanisms of PASC. CPET data can be used to calculate rates of β-oxidation of fatty acids (FATox) and of lactate clearance, providing insight into mitochondrial function (). Fit individuals have better mitochondrial function and a higher rate of FATox during exercise than less fit individuals (). Our results suggest that patients with PASC have significant impairment in fat β-oxidation and increased blood lactate accumulation during exercise, regardless of previous comorbidities.

Read the rest of this article HERE.

Source: de Boer, E., Petrache, I., Goldstein, N. M., Olin, J. T., Keith, R. C., Modena, B., Mohning, M. P., Yunt, Z. X., San-Millán, I., & Swigris, J. J. (2022). Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome. American journal of respiratory and critical care medicine, 205(1), 126–129. https://doi.org/10.1164/rccm.202108-1903LE  I https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865580/ (Full text)

Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain

Abstract:

Chronic pain associated with fibromyalgia (FM) affects a large portion of the population but the underlying mechanisms leading to this altered pain are still poorly understood. Evidence suggests that FM involves altered neural processes in the central nervous system and neuroimaging methods such as functional magnetic resonance imaging (fMRI) are used to reveal these underlying alterations. While many fMRI studies of FM have been conducted in the brain, recent evidence shows that the changes in pain processing in FM may be linked to autonomic and homeostatic dysregulation, thus requiring further investigation in the brainstem and spinal cord.

Functional magnetic resonance imaging data from 15 women with FM and 15 healthy controls were obtained in the cervical spinal cord and brainstem at 3 tesla using previously established methods. In order to investigate differences in pain processing in these groups, participants underwent trials in which they anticipated and received a predictable painful stimulus, randomly interleaved with trials with no stimulus. Differences in functional connectivity between the groups were investigated by means of structural equation modeling.

The results demonstrate significant differences in brainstem/spinal cord network connectivity between the FM and control groups which also correlated with individual differences in pain responses. The regions involved in these differences in connectivity included the LC, hypothalamus, PAG, and PBN, which are known to be associated with autonomic homeostatic regulation, including fight or flight responses. This study extends our understanding of altered neural processes associated with FM and the important link between sensory and autonomic regulation systems in this disorder.

Source: Ioachim G, Warren HJM, Powers JM, Staud R, Pukall CF, Stroman PW. Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain. Front Neurol. 2022 May 6;13:862976. doi: 10.3389/fneur.2022.862976. PMID: 35599729; PMCID: PMC9120571. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120571/ (Full text)

Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET

Abstract:

A significant number of COVID-19 patients develop ‘long COVID’, a condition defined by long-lasting debilitating, often neurological, symptoms. The pathophysiology of long COVID is unknown. Here we present in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment, [18F]DPA-714 PET, in two long COVID patients. We reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in [18F]DPA-714 binding throughout the brain. Quantitative measures of binding (BPND values) were increased on average by 121% and 76%, respectively. This implicates profound neuroinflammation in the pathophysiology of long COVID.

Source: Denise Visser, Sandeep S.V. Golla, Sander C.J. Verfaillie, Emma M. Coomans, Roos M. Rikken, Elsmarieke M. van de Giessen, Marijke E. den Hollander, Anouk Verveen, Maqsood Yaqub, Frederik Barkhof, Janneke Horn, Bart Koopman, Patrick Schober, Dook W. Koch, Robert C. Schuit, Albert D. Windhorst, Michael Kassiou, Ronald Boellaard, Michele van Vugt, Hans Knoop, Nelleke Tolboom, Bart N.M. van Berckel. Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET. medRxiv 2022.06.02.22275916; doi: https://doi.org/10.1101/2022.06.02.22275916 https://www.medrxiv.org/content/10.1101/2022.06.02.22275916v1.full-text (Full text)

Symptom burden correlates to impairment of diffusion capacity and exercise intolerance in long COVID patients

Abstract:

After acute infection with the SARS-CoV-2 virus, a considerable number of patients remains symptomatic with pathological changes in various organ systems. This study aimed to relate the physical and mental burden of symptoms of long COVID patients to the findings of a somatic evaluation.

In patients with persistent long COVID symptoms three months after acute infection we assessed physical and mental health status using the SF-36 questionnaire. The cohort was dichotomised by the results (upper two quartiles vs. lower to quartiles) and compared with regard to transthoracic echocardiography, body plethysmography (including diffusion capacity), capillary blood gas analysis and 6-min walk test (6-MWT). From February 22 to September 13, 2021, 463 patients were prospectively examined, of which 367 completed the SF-36 questionnaire. A positive correlation between initial disease severity (need for hospitalization, intensive care medicine) and resulting symptom burden at follow-up could be demonstrated.

Patients with impaired subjective physical and mental status were significantly more likely to be women. There was a significant correlation between symptom severity and reduced exercise tolerance in the 6-MWT (495.6 ± 83.7 m vs 549.7 ± 71.6 m, p < 0.001) and diffusion capacity for carbon monoxide (85.6 ± 14.3% of target vs 94.5 ± 14.4, p < 0.001). In long COVID patients, initial disease severity is correlated with symptom burden after at least 3 months of follow-up. Highly symptomatic long COVID patients show impaired diffusion capacity and 6-MWT despite average or mildly affected mechanical lung parameters. It must be further differentiated whether this corresponds to a transient functional impairment or whether it is a matter of defined organ damage.

Source: Kersten, J., Wolf, A., Hoyo, L. et al. Symptom burden correlates to impairment of diffusion capacity and exercise intolerance in long COVID patients. Sci Rep 12, 8801 (2022). https://doi.org/10.1038/s41598-022-12839-5  https://www.nature.com/articles/s41598-022-12839-5 (Full text)

Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients

Abstract:

Introduction. The severity and prevalence of Post-Acute COVID-19 Sequela (PACS) or long-COVID syndrome (long COVID) should not be a surprise. Long-COVID symptoms may be explained by oxidative stress and parasympathetic and sympathetic (P&S) dysfunction. This is a retrospective, hypothesis generating, outcomes study.
Methods. From two suburban practices in northeastern United States, 152 long COVID patients were exposed to the following practices: (1) first, they were P&S tested (P&S Monitor 4.0; Physio PS, Inc., Atlanta, GA, USA) prior to being infected with COVID-19 due to other causes of autonomic dysfunction; (2) received a pre-COVID-19 follow-up P&S test after autonomic therapy; (3) then, they were infected with COVID-19; (4) P&S tested within three months of surviving the COVID-19 infection with long-COVID symptoms; and, finally, (5) post-COVID-19, follow-up P&S tested, again, after autonomic therapy. All the patients completed autonomic questionnaires with each test. This cohort included 88 females (57.8%), with an average age of 47.0 years (ranging from 14 to 79 years), and an average BMI of 26.9 #/in2. Results. More pre-COVID-19 patients presented with sympathetic withdrawal than parasympathetic excess. Post-COVID-19, these patients presented with this ratio reversed and, on average, 49.9% more autonomic symptoms than they did pre-COVID-19.
Discussion. Both parasympathetic excess and sympathetic withdrawal are separate and treatable autonomic dysfunctions and autonomic treatment significantly reduces the prevalence of autonomic symptoms.
Conclusion. SARS-CoV-2, via its oxidative stress, can lead to P&S dysfunction, which, in turn, affects the control and coordination of all systems throughout the whole body and may explain all of the symptoms of long-COVID syndrome. Autonomic therapy leads to positive outcomes and patient quality of life may be restored.
Source: Colombo J, Weintraub MI, Munoz R, Verma A, Ahmad G, Kaczmarski K, Santos L, DePace NL. Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients. NeuroSci. 2022; 3(2):300-310. https://doi.org/10.3390/neurosci3020021 https://www.mdpi.com/2673-4087/3/2/21/htm (Full text)

Long COVID after breakthrough SARS-CoV-2 infection

Abstract:

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear.

In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders.

The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.

Source: Al-Aly, Z., Bowe, B. & Xie, Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med (2022). https://doi.org/10.1038/s41591-022-01840-0  https://www.nature.com/articles/s41591-022-01840-0 (Full text)

Impaired Vagal Activity in Long-COVID-19 Patients

Abstract:

Long-COVID-19 refers to the signs and symptoms that continue or develop after the “acute COVID-19” phase. These patients have an increased risk of multiorgan dysfunction, readmission, and mortality. In Long-COVID-19 patients, it is possible to detect a persistent increase in D-Dimer, NT-ProBNP, and autonomic nervous system dysfunction.

To verify the dysautonomia hypothesis in Long-COVID-19 patients, we studied heart rate variability using 12-lead 24-h ECG monitoring in 30 Long-COVID-19 patients and 20 No-COVID patients. Power spectral analysis of heart rate variability was lower in Long-COVID-19 patients both for total power (7.46 ± 0.5 vs. 8.08 ± 0.6; p &lt; 0.0001; Cohens-d = 1.12) and for the VLF (6.84 ± 0.8 vs. 7.66 ± 0.6; p &lt; 0.0001; Cohens-d = 1.16) and HF (4.65 ± 0.9 vs. 5.33 ± 0.9; p = 0.015; Cohens-d = 0.76) components. The LF/HF ratio was significantly higher in Long-COVID-19 patients (1.46 ± 0.27 vs. 1.23 ± 0.13; p = 0.001; Cohens-d = 1.09). On multivariable analysis, Long-COVID-19 is significantly correlated with D-dimer (standardized β-coefficient = 0.259), NT-ProBNP (standardized β-coefficient = 0.281), HF component of spectral analysis (standardized β-coefficient = 0.696), and LF/HF ratio (standardized β-coefficient = 0.820).

Dysautonomia may explain the persistent symptoms in Long COVID-19 patients. The persistence of a procoagulative state and an elevated myocardial strain could explain vagal impairment in these patients. In Long-COVID-19 patients, impaired vagal activity, persistent increases of NT-ProBNP, and a prothrombotic state require careful monitoring and appropriate intervention.

Source: Acanfora D, Nolano M, Acanfora C, Colella C, Provitera V, Caporaso G, Rodolico GR, Bortone AS, Galasso G, Casucci G. Impaired Vagal Activity in Long-COVID-19 Patients. Viruses. 2022 May 13;14(5):1035. doi: 10.3390/v14051035. PMID: 35632776; PMCID: PMC9147759. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9147759/ (Full text)

Clearance of Persistent SARS-CoV-2 RNA Detection in a NFκB-Deficient Patient in Association with the Ingestion of Human Breast Milk: A Case Report

Abstract:

Currently, there are no evidence-based treatment options for long COVID-19, and it is known that SARS-CoV-2 can persist in part of the infected patients, especially those with immunosuppression. Since there is a robust secretion of SARS-CoV-2-specific highly-neutralizing IgA antibodies in breast milk, and because this immunoglobulin plays an essential role against respiratory virus infection in mucosa cells, being, in addition, more potent in neutralizing SARS-CoV-2 than IgG, here we report the clinical course of an NFκB-deficient patient chronically infected with the SARS-CoV-2 Gamma variant, who, after a non-full effective treatment with plasma infusion, received breast milk from a vaccinated mother by oral route as treatment for COVID-19. After such treatment, the symptoms improved, and the patient was systematically tested negative for SARS-CoV-2. Thus, we hypothesize that IgA and IgG secreted antibodies present in breast milk could be useful to treat persistent SARS-CoV-2 infection in immunodeficient patients.

Source: Sabino JS, Amorim MR, de Souza WM, Marega LF, Mofatto LS, Toledo-Teixeira DA, Forato J, Stabeli RG, Costa ML, Spilki FR, Sabino EC, Faria NR, Benites BD, Addas-Carvalho M, Stucchi RSB, Vasconcelos DM, Weaver SC, Granja F, Proenca-Modena JL, Vilela MMDS. Clearance of Persistent SARS-CoV-2 RNA Detection in a NFκB-Deficient Patient in Association with the Ingestion of Human Breast Milk: A Case Report. Viruses. 2022 May 13;14(5):1042. doi: 10.3390/v14051042. PMID: 35632784; PMCID: PMC9143223. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143223/ (Full text)