Rheumatology and Long COVID: lessons from the study of fibromyalgia

Abstract:

Rheumatology, such as other subspecialties, has both a unique perspective to offer as well as an evolving role to play in the global COVID-19 pandemic. Our field has already contributed meaningfully to the development and repurposing of many of the immune-based therapeutics which are now standard treatments for severe forms of the disease as well as to the understanding of the epidemiology, risk factors and natural history of COVID-19 in immune-mediated inflammatory diseases. Still in evolution is our potential to contribute to burgeoning research efforts in the next phase of the pandemic: the syndrome of postacute sequelae of COVID-19 or Long COVID. While our field brings many assets to the study of Long COVID including our expertise in the investigation of chronic inflammation and autoimmunity, our Viewpoint focuses on the strong similarities between fibromyalgia (FM) and Long COVID. While one can speculate on how embracing and confident practising rheumatologists already are regarding these interrelationships, we assert that in the emerging field of Long COVID the potential lessons from the field of fibromyalgia care and research have been underappreciated and marginalised and most importantly now deserve a critical appraisal.

Source: Clauw DJ, Calabrese L. Rheumatology and Long COVID: lessons from the study of fibromyalgia. Ann Rheum Dis. 2023 May 25:ard-2023-224250. doi: 10.1136/ard-2023-224250. Epub ahead of print. PMID: 37230736. https://ard.bmj.com/content/early/2023/05/24/ard-2023-224250 (Full text)

Autonomic Nervous System Affection Due to Post Covid Syndrome

Identification of the Effects of Post Covid Syndrome on the Autonomic Nervous System With Heart Rate Variability

Post-Covid syndrome is defined as symptoms that develop in addition to respiratory symptoms in individuals who have had Covid-19 infection for more than 12 weeks. Symptoms such as fatigue, headache, cognitive impairment, dyspnea, heart palpitations, heat intolerance, digestive system disorders, sleep disorders, dermal problems, orthostatic intolerance come to the fore in individuals with post-Covid syndrome. It has been tried to be revealed in some studies that Covid-19 infection affects the autonomic nervous system (ANS) and the relationship between Post-Covid 19 syndrome and ANS dysfunction.
Heart rate variability (HRV) measurement method can be used to evaluate ANS activity. HRV is a non-invasive method and is a measure of the change in heart rate over a period of time. HRV is a scalar quantity that shows the time between two beats of the heart and defines the oscillations between the R-R intervals. In HRV measurements, time-dependent and frequency-dependent measurement results are obtained and from these measurements, time-dependent RMSSD (square root of the square of the difference of the R-R intervals) and frequency-dependent high-frequency (HF) and low frequency (LF) measurement components are used in relation to the sympathetic nervous system (CNS) and parasympathetic nervous system (PSS). HRV can be measured in short-term (5 minutes) in terms of measurement time.
The aim of this study is to clearly reveal the relationship between Post-Covid 19 syndrome and ANS dysfunction and to provide standardization related to HRV measurement method and sub-parameters.
Source: Ali Veysel Özden, M.D. Bahçeşehir University. Istanbul, Beşiktaş, Turkey, 34000. ICH GCP US Clinical Trials Registry, Clinical Trial NCT05502094 https://ichgcp.net/clinical-trials-registry/NCT05502094

Changes in the proteomics of exhaled breath condensate under the influence of inhaled hydrogen in patients with post-COVID syndrome.

Abstract:

Purpose. To study the effect of inhalation therapy with an active form of hydrogen (APH) on the protein composition of exhaled air condensate (EAC) in patients with post-COVID syndrome (PCS).

Material and methods. A randomized controlled parallel prospective study included 60 patients who had a novel coronavirus infection (COVID-19, COronaVIrus Disease 2019) with PCD during the recovery period, had clinical manifestations of chronic fatigue syndrome and received standard therapy according to the protocol for managing patients with chronic fatigue syndrome. The patients were divided into 2 groups: group 1 (main) – 30 people who received standard therapy and APV inhalations (device “SUISONIA”, Japan) for 10 days, and group 2 (control) – 30 medical workers who received only standard therapy. Patients in both groups were comparable in terms of gender and mean age. All participants in the study on the 1st and 10th days. samples were taken from the CVV.

Results. A total of 478 proteins and 1350 peptides were identified using high resolution mass spectrometry. The number of proteins in samples after APV therapy, on average, is 12% more than before treatment. An analysis of the distribution of proteins in different groups of patients showed that only half of these proteins (112) are common for all groups of samples and are detected in EVC before, after, and regardless of hydrogen therapy. In addition to the qualitative difference in the protein compositions of CEA in different groups, quantitative changes in the concentration of 36 proteins (mainly structural and protective) were also detected, which together made it possible to reliably distinguish between subgroups before and after treatment. It is important to note that among these proteins there are participants in the processes of blood coagulation (a-1-antitrypsin), mediated by chemokines and cytokines of inflammation,

Conclusion. The use of hydrogen therapy can contribute to the switching of a number of physiological processes, which may affect the success of restorative treatment in PKD. In particular, the obtained results indicate the activation of aerobic synthesis of adenosine triphosphate in mitochondria by hydrogen therapy, which correlates well with the decrease in blood lactate levels detected by laboratory studies in the studied patients. At the same time, it is important that this therapy can inhibit pro-inflammatory activity, negatively affecting the coagulation processes and signaling pathways of integrins and apoptosis, and, in addition, activate protective pathways, the tricarboxylic acid cycle, FAS signaling, and purine metabolism, which can be significant. for effective recovery after suffering COVID-19.

Source: Ryabokon, A. M.; Zakharova, N. V.; Indeikina, M. I.; Kononikhin, A. S.; Shogenova, L. V.; Medvedev, O. S.; Kostinov, M. P.; Svitich, O. A.; Ibaraki, K.; Maehara, H.; Nikolaev, E. N.; Varfolomeev, S. D.; Chuchalin, A. G. Changes in the proteomics of exhaled breath condensate under the influence of inhaled hydrogen in patients with post-COVID syndrome. Cardiovascular Therapy and Prevention (Russian Federation) ; 22(3):50-59, 2023. https://www.researchgate.net/publication/369954717_Changes_in_the_proteomics_of_exhaled_breath_condensate_under_the_influence_of_inhaled_hydrogen_in_patients_with_post-COVID_syndrome

Effects of whole-body cryotherapy and static stretching are maintained 4 weeks after treatment in most patients with chronic fatigue syndrome

Abstract

In the previous study, whole-body cryotherapy (WBC)+static stretching (SS) has been shown to reduce the severity of some symptoms in Chronic Fatigue Syndrome (CFS) noted just after the therapy. Here we consider the effects of treatment and explore the sustainability of symptom improvements at four weeks (one-month) follow-up.

Twenty-two CFS patients were assessed one month after WBC + SS programme. Parameters related to fatigue (Chalder Fatigue Questionnaire (CFQ), Fatigue Impact Scale (FIS), Fatigue Severity Scale (FSS)), cognitive function (Trial Making test part A and B (TMT A and TMT B and its difference (TMT B-A)), Coding) hemodynamic, aortic stiffness (aortic systolic blood pressure (sBP aortic)) and autonomic nervous system functioning were measured. TMT A, TMT B, TMT B-A and Coding improved at one month after the WBC + SS programme.

WBC + SS had a significant effect on the increase in sympathetic nervous system activity in rest. WBC + SS had a significant, positive chronotropic effect on the cardiac muscle. Peripheral and aortic systolic blood pressure decreased one month after WBC + SS in comparison to before.

Effects of WBC + SS on reduction of fatigue, indicators of aortic stiffness and symptoms severity related to autonomic nervous system disturbance and improvement in cognitive function were maintained at one month.

However, improvement in all three fatigue scales (CFQ, FIS and FSS) was noted in 17 of 22 patients. In addition, ten patients were treated initially but they were not assessed at 4 weeks, and are thus not included in the 22 patients who were examined on follow-up. The overall effects of WBC + SS noted at one month post-treatment should be interpreted with caution.

Source: Kujawski S, Zalewski P, Godlewska BR, Cudnoch-Jędrzejewska A, Murovska M, Newton JL, Sokołowski Ł, Słomko J. Effects of whole-body cryotherapy and static stretching are maintained 4 weeks after treatment in most patients with chronic fatigue syndrome. Cryobiology. 2023 May 23:S0011-2240(23)00035-4. doi: 10.1016/j.cryobiol.2023.05.003. Epub ahead of print. PMID: 37230457. https://www.sciencedirect.com/science/article/pii/S0011224023000354?via%3Dihub (Full text)

Fighting Post-COVID and ME/CFS – development of curative therapies

Abstract:

The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as potential mechanisms.

However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

No curative therapies are available for neither ME/CFS nor PCS. The mechanisms identified so far provide targets for therapeutic interventions.

To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.

Source: Carmen Scheibenbogen, Judith T. Bellmann-Strobl, Cornelia Heindrich, Kirsten Wittke, Elisa Stein, Christiana Franke, Harald Prüss, Hannah Preßler, Marie-Luise Machule, Heinrich Audebert, Carsten Finke, Hanna G. Zimmerman,  Birgit Sawitzki, Christian Meisel, Markus Tölle, Anne Krüger, Anna C. Aschenbrenner, Joachim L. Schultz, Marc D. Beyer, Markus Ralser, Michael Mülleder, Leif E. Sander, Frank Konietschke, Friedemann Paul, Silvia Stojanov, Lisa Bruckert, Dennis M. Hedderich, Franziska Knolle, Gabriela Riemekasten, Maria J. Vehreschild, Oliver A. Cornely, Uta Behrends and Susen Burock.  Fighting Post-COVID and ME/CFS – development of curative therapies. Frontiers in Medicine, Sec. Infectious Diseases: Pathogenesis and Therapy: Volume 10 – 2023. https://www.frontiersin.org/articles/10.3389/fmed.2023.1194754/abstract

 

Identifying Demographic Trends in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients Presenting with Fibromyalgia as a Comorbidity in the Nationwide Inpatient Sample Database

Abstract

This retrospective observational study investigates the demographic differences between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients with and without Fibromyalgia as a comorbidity using the Nationwide Inpatient Sample database.

Results reveal significant differences in demographics, including a higher proportion of females and a younger mean age in the Fibromyalgia group. Additionally, the Fibromyalgia group had lower in-hospital mortality, higher proportion of patients discharged home or to short-term hospitals, shorter lengths of stay, and lower hospital charges.

Despite having lower Elixhauser comorbidity scores, ME/CFS patients with Fibromyalgia had higher prevalence of certain conditions.

Limitations include missing data, and further research is warranted to refine ME/CFS definitions and develop personalized treatment plans. The study highlights the need for better understanding of ME/CFS mechanisms, correlations with comorbidities like Fibromyalgia, and potential predictors to improve diagnosis and treatment.

Source: Arvind Vishnu Murali. Identifying Demographic Trends in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients Presenting with Fibromyalgia as a Comorbidity in the Nationwide Inpatient Sample Database. Icahn School of Medicine at Mount Sinai ProQuest Dissertations Publishing,  2023. 30494377. https://www.proquest.com/openview/12cb80c96056a220f9e1d8bd7ea5fecc/1?pq-origsite=gscholar&cbl=18750&diss=y

Investigating antibody reactivity to the intestinal microbiome in severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystemic disease of unknown aetiology that is characterised by disabling chronic fatigue and involves both the immune and gastrointestinal (GI) systems. Patients display alterations in GI microbiome with a significant proportion experiencing GI discomfort and pain and elevated blood biomarkers for altered intestinal permeability compared with healthy individuals.

To investigate a possible GI origin of ME/CFS we designed a feasibility study to test the hypothesis that ME/CFS pathogenesis is a consequence of increased intestinal permeability that results in microbial translocation and a breakdown in immune tolerance leading to generation of antibodies reactive to indigenous intestinal microbes. Secretory IgA and serum IgG levels and reactivity to intestinal microbes were assessed in five pairs of severe ME/CFS patients and matched same-household healthy controls. For profiling serum IgG we developed IgG-Seq which combines flow-cytometry based bacterial cell sorting and metagenomics to detect mucosal IgG reactivity to the microbiome.

We uncovered evidence for immune dysfunction in severe ME/CFS patients that was characterised by reduced capacity and reactivity of serum IgG to stool microbes, irrespective of their source. This study provides the rationale for additional studies in larger cohorts of ME/CFS patients to further explore immune-microbiome interactions.

Source: Katharine A. Seton, Marianne Defernez, Andrea Telatin, Sumeet K. Tiwari, George M. Savva, Antonietta Hayhoe, Alistair Noble, Ana Carvalho, Steve James, Amolak Bansal, Thomas Wileman, Simon R. Carding. Investigating antibody reactivity to the intestinal microbiome in severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). medRxiv 2023.05.21.23290299; doi: https://doi.org/10.1101/2023.05.21.23290299 https://www.medrxiv.org/content/10.1101/2023.05.21.23290299v1.full-text (Full text)

ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature

Summary:

Some patients remain unwell for months after “recovering” from acute COVID-19. They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance and other symptoms that greatly interfere with their ability to function and that can leave some people housebound and disabled. The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as to persisting illnesses that can follow a wide variety of other infectious agents and following major traumatic injury. Together, these illnesses are projected to cost the U.S. trillions of dollars.

In this review, we first compare the symptoms of ME/CFS and Long COVID, noting the considerable similarities and the few differences. We then compare in extensive detail the underlying pathophysiology of these two conditions, focusing on abnormalities of the central and autonomic nervous system, lungs, heart, vasculature, immune system, gut microbiome, energy metabolism and redox balance. This comparison highlights how strong the evidence is for each abnormality, in each illness, and helps to set priorities for future investigation. The review provides a current road map to the extensive literature on the underlying biology of both illnesses.

Source: Anthony L. Komaroff and W. Ian Lipkin. ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature. Front. Med., 02 June 2023. Sec. Infectious Diseases: Pathogenesis and Therapy. Volume 10 – 2023 | https://doi.org/10.3389/fmed.2023.1187163 (Full text)

Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms

Abstract:

Importance: Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.

Objective: To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.

Design, setting, and participants: This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.

Main outcomes and measures: The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.

Results: The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, -0.53; 95% CI, -0.79 to -0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).

Conclusions and relevance: In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.

Source: Braga J, Lepra M, Kish SJ, Rusjan PM, Nasser Z, Verhoeff N, Vasdev N, Bagby M, Boileau I, Husain MI, Kolla N, Garcia A, Chao T, Mizrahi R, Faiz K, Vieira EL, Meyer JH. Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms. JAMA Psychiatry. 2023 May 31:e231321. doi: 10.1001/jamapsychiatry.2023.1321. Epub ahead of print. PMID: 37256580; PMCID: PMC10233457. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10233457/ (Full text)

Childhood trauma as a risk factor for a dysfunctional heart rate variability in patients with CFS/ME

Background: Myalgic encephalomyelitis, also called Chronic Fatigue Syndrome or ME/CFS, is a severe and complex multisystemic disease with a heterogenous combination of symptoms. Studies have shown decreased heart rate variability (HRV) in this population. Moreover, there is a growing body of evidence showing high levels of childhood trauma (CHT) among ME/CFS patients. Traumatic experiences in childhood are linked to a decreased HRV. Specially, emotional traumatization impacts HRV. The present study investigates HRV in the context of CHT in a ME/CFS population.

Methods 37 patients diagnosed with ME/CFS participated in this study. Demographic-, clinical data, the degree of disability, and RMSSD parameters of HRV were extracted from patient records. HRV data was gathered over 30 minutes whilst in supine position. CHT was administered using the Childhood Trauma Questionnaire-Short Form. Disability was assessed using the Bell Disability Scale. Multiple regression analyses were conducted using the CHT total scores and emotional abuse and emotional neglect subscales in relation to HRV.

Results Variables / Research Materials Data / Observations Results • Fig.5 HRV in the Monitoring compare the interaction between VNS Sympathic Frequency (LF 0.04-0.15) and Parasympathic Frequency (HF 0.15-0.50) in four stages: Orthostatic Schellong Test, start of the Monitoring in lying down position, Middle section after 15 Minutes and after 30 Minutes. • Box-Plot Data shows the most fluctuation of Sympathic in the middle section. The highest scores and fluctuation which appear of Parasympathic activity is in the beginning of the measurement.

Conclusion • In sum, the results of the study suggest that CHT is more prevalent in ME/CFS populations. However, an effect of childhood trauma on HRV function and disability could not be demonstrated in this sample. The findings indicate that the underlying pathophysiologic mechanism of CHT in ME/CFS are more complex and not expressed in HRV. Future studies should include additional aspects and examine the impact of childhood trauma by looking at other biological systems affected in ME/CFS.

Works Cited • Cohen, J. (1988) Statistical power analysis for the behavioral sciences, New York second edition.

Source: Ziaja, Christof, Young, Susanne, Sadre Chirazi – Stark, Michael.Childhood trauma as a risk factor for a dysfunctional heart rate variability in patients with CFS/ME. 2023/05/24 DOI:10.13140/RG.2.2.17700.65929 https://www.researchgate.net/publication/370987476_Childhood_trauma_as_a_risk_factor_for_a_dysfunctional_heart_rate_variability_in_patients_with_CFSME