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 

Could vascular damage caused by massive inflammatory events underlie a relapse/recovery phenotype of ME/CFS and Long COVID?

Abstract:

I hypothesize that there is a relapse/recovery type of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID in which a massive inflammatory event—like the inflammatory cascade prompted by the restoration of blood flow (reperfusion) to tissue that had been deprived of blood (ischemia) or an allergic or pseudoallergic reaction—causes substantial damage to blood vessels, launching a more severe phase of ME/CFS.
People with Ehlers-Danlos syndrome and other connective tissue disorders may be at particular risk of this phenotype due to having connective tissue (a key component of blood vessels) that is more easily and severely injured during inflammatory events and slower to heal, causing a much longer recovery.

Source: Tamara Carnac. Could vascular damage caused by massive inflammatory events underlie a relapse/recovery phenotype of ME/CFS and Long COVID? Patient-Generated Hypotheses Journal | Issue 1, May 2023. https://patientresearchcovid19.com/storage/2023/05/Patient-Generated-Hypotheses-Issue-1-May-2023.pdf#page=30 (Full text)

Chronic Fatigue Syndrome and Multiple Sclerosis have Reduced Craniospinal Compliance and Dilated Pressurized Bridging Cortical Veins: A Hypothesis Illustrated with Two Case Studies

Abstract:

Chronic fatigue syndrome (CFS) and multiple sclerosis (MS) share similarities regarding their epidemiology, symptomatology and craniospinal physiology. Indeed, the cardinal feature of CFS, fatigue, is also a major factor in the symptomatology of the majority of MS patients.

Recently, we have found that there is a significant reduction in the craniospinal compliance in MS which affects both the stiffness of the walls of the spinal canal and the walls of the cerebral venous system. This change in compliance brings about an alteration in the effectiveness of the pulse wave dampening in the craniospinal system. The result is an impedance mismatch between the cortical veins and their draining sinuses, leading to dilatation of these upstream veins.

We deduce this dilatation can only be brought about by an increase in the pressure gradient between the vein lumen and the subarachnoid space (i.e. the transmural pressure gradient). We hypothesise that given the similarities between MS and CFS, a similar mechanism underlies the physiology of CFS. We present two case studies to highlight the expected findings in CFS patients if this hypothesis were proven to be correct.

Source: Bateman, G.; Bateman, A. Chronic Fatigue Syndrome and Multiple Sclerosis have Reduced Craniospinal Compliance and Dilated Pressurized Bridging Cortical Veins: A Hypothesis Illustrated with Two Case Studies. Preprints.org 2023, 2023052264. https://doi.org/10.20944/preprints202305.2264.v1 https://www.preprints.org/manuscript/202305.2264/v1 (Full text available as PDF file)

Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study

Abstract:

Objective: To evaluate longer term symptoms and health outcomes associated with post-covid-19 condition within a cohort of individuals with a SARS-CoV-2 infection.

Design: Population based, longitudinal cohort.

Setting: General population of canton of Zurich, Switzerland.

Participants: 1106 adults with a confirmed SARS-CoV-2 infection who were not vaccinated before infection and 628 adults who did not have an infection.

Main outcome measures: Trajectories of self-reported health status and covid-19 related symptoms between months six, 12, 18, and 24 after infection and excess risk of symptoms at six months after infection compared with individuals who had no infection.

Results: 22.9% (95% confidence interval 20.4% to 25.6%) of individuals infected with SARS-CoV-2 did not fully recover by six months. The proportion of individuals who had an infection who reported not having recovered decreased to 18.5% (16.2% to 21.1%) at 12 months and 17.2% (14.0% to 20.8%) at 24 months after infection. When assessing changes in self-reported health status, most participants had continued recovery (68.4% (63.8% to 72.6%)) or had an overall improvement (13.5% (10.6% to 17.2%)) over time. Yet, 5.2% (3.5% to 7.7%) had a worsening in health status and 4.4% (2.9% to 6.7%) had alternating periods of recovery and health impairment. The point prevalence and severity of covid-19 related symptoms also decreased over time, with 18.1% (14.8% to 21.9%) reporting symptoms at 24 months. 8.9% (6.5% to 11.2%) of participants reported symptoms at all four follow-up time points, while in 12.5% (9.8% to 15.9%) symptoms were alternatingly absent and present. Symptom prevalence was higher among individuals who were infected compared with those who were not at six months (adjusted risk difference 17.0% (11.5% to 22.4%)). Excess risk (adjusted risk difference) for individual symptoms among those infected ranged from 2% to 10%, with the highest excess risks observed for altered taste or smell (9.8% (7.7% to 11.8%)), post-exertional malaise (9.4% (6.1% to 12.7%)), fatigue (5.4% (1.2% to 9.5%)), dyspnoea (7.8% (5.2% to 10.4%)), and reduced concentration (8.3% (6.0% to 10.7%)) and memory (5.7% (3.5% to 7.9%)).

Conclusions: Up to 18% of individuals who were not vaccinated before infection had post-covid-19 condition up to two years after infection, with evidence of excess symptom risk compared with controls. Effective interventions are needed to reduce the burden of post-covid-19 condition. Use of multiple outcome measures and consideration of the expected rates of recovery and heterogeneity in symptom trajectories are important in the design and interpretation of clinical trials.

Registrations: ISRCTN18181860

Source: Ballouz T, Menges D, Anagnostopoulos A, Domenghino A, Aschmann HE, Frei A, Fehr JS, Puhan MA. Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study. BMJ. 2023 May 31;381:e074425. doi: 10.1136/bmj-2022-074425. PMID: 37257891. https://www.bmj.com/content/381/bmj-2022-074425 (Full text)

‘Welcome to my world’: a thematic analysis of the lived experiences of people with Myalgic Encephalomyelitis during the UK COVID-19 lockdown

Abstract:

Objectives: We explore the experiences of people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (pwME/CFS) during the first UK COVID-19 lockdown period. We specifically probe perceived commonalities and departures in experience between government- and health-imposed lockdowns, application of coping strategies for social isolation, and predictions for inclusion of the chronically ill in post-pandemic society.

Methods and measures: Thirty semi-structured interviews were conducted in pwME/CFS between June – July, 2020. Responses were qualitatively analysed using an experiential, thematic framework.

Results: While participants reported enhancements in digital accessibility during lockdown, they perceived this as an unintentional benefit from changes designed to cater universally. Similarly, their expectation was that the general population’s limited experience of restriction would not engender greater understanding for those who would continue to experience health-imposed lockdowns, post-pandemic. Participants described numerous strategies for coping with restriction and isolation, developed during prior health-imposed lockdowns and applied to this novel circumstance, highlighting the presence of acceptance and resilience in the sample.

Conclusions: Our findings suggest that future work may fruitfully examine whether our participant’s predictions for post-pandemic societal inclusion have been met, and how resilience and acceptance might be developed and nurtured in chronically ill populations through times of adversity.

Source:Portch E, Moseley RL, Wignall L, Turner-Cobb JM, Taylor Z, Gondelle M. ‘Welcome to my world’: a thematic analysis of the lived experiences of people with Myalgic Encephalomyelitis during the UK COVID-19 lockdown. Psychol Health. 2023 May 31:1-18. doi: 10.1080/08870446.2023.2220009. Epub ahead of print. PMID: 37259524. https://pubmed.ncbi.nlm.nih.gov/37259524/

Alcohol intolerance and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: The literature is mixed about the occurrence of alcohol intolerance among patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Surveys that asked respondents with ME/CFS whether they experienced alcohol intolerance within a recent time frame might produce inaccurate results because respondents may indicate that the symptom was not present if they avoid alcohol due to alcohol intolerance.

AIM: To overcome this methodologic problem, participants in the current study were asked whether they have avoided alcohol in the past 6 mo, and if they had, how severe their alcohol intolerance would be if they were to drink alcohol.

METHODS: The instrument used was a validated scale called the DePaul symptom questionnaire. Independent t-tests were performed among the alcohol intolerant or not alcohol intolerant group. The alcohol intolerant group had 208 participants, and the not alcohol intolerant group had 96 participants.

RESULTS: Using specially designed questions to properly identify those with alcohol intolerance, those who experienced alcohol intolerance vs those who did not experience alcohol intolerance experienced more frequent/severe symptoms and domains. In addition, using a multiple regression analysis, the orthostatic intolerance symptom domain was related to alcohol intolerance.

CONCLUSION: The findings from the current study indicated that those with ME/CFS are more likely to experience alcohol intolerance. In addition, those with this symptom have more overall symptoms than those without alcohol intolerance.

Source: Maciuch J, Jason LA. Alcohol intolerance and myalgic encephalomyelitis/chronic fatigue syndrome. World J Neurol 2023; 9(3): 17-27 [DOI: 10.5316/wjn.v9.i3.17] https://www.wjgnet.com/2218-6212/full/v9/i3/17.htm (Full text)

Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study

Abstract:

COVID-19-associated vascular disease complications are primarily associated with endothelial dysfunction; however, the consequences of disease on vascular structure and function, particularly in the long term (>7 weeks post-infection), remain unexplored. Individual pre- and post-infection changes in arterial stiffness as well as central and systemic hemodynamic parameters were measured in patients diagnosed with mild COVID-19.
As part of in-laboratory observational studies, baseline measurements were taken up to two years before, whereas the post-infection measurements were made 2–3 months after the onset of COVID-19. We used the same measurement protocol throughout the study as well as linear and mixed-effects regression models to analyze the data. Patients (N = 32) were predominantly healthy and young (mean age ± SD: 36.6 ± 12.6). We found that various parameters of arterial stiffness and central hemodynamics—cfPWV, AIx@HR75, and cDBP as well as DBP and MAP—responded to a mild COVID-19 disease.
The magnitude of these responses was dependent on the time since the onset of COVID-19 as well as age (pregression_models ≤ 0.013). In fact, mixed-effects models predicted a clinically significant progression of vascular impairment within the period of 2–3 months following infection (change in cfPWV by +1.4 m/s, +15% in AIx@HR75, approximately +8 mmHg in DBP, cDBP, and MAP).
The results point toward the existence of a widespread and long-lasting pathological process in the vasculature following mild COVID-19 disease, with heterogeneous individual responses, some of which may be triggered by an autoimmune response to COVID-19.
Source: Podrug M, Koren P, Dražić Maras E, Podrug J, Čulić V, Perissiou M, Bruno RM, Mudnić I, Boban M, Jerončić A. Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study. Journal of Clinical Medicine. 2023; 12(6):2123. https://doi.org/10.3390/jcm12062123 https://www.mdpi.com/2077-0383/12/6/2123 (Full text)

Comparison of a 20 degree and 70 degree tilt test in adolescent myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients

Abstract:

Introduction: During a standard 70-degree head-up tilt test, 90% of adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develop an abnormal reduction in cerebral blood flow (CBF). A 70-degree test might not be tolerated by young ME/CFS patients because of the high incidence of syncopal spells. This study examined whether a test at 20 degrees would be sufficient to provoke important reductions in CBF in young ME/CFS patients.

Methods: We analyzed 83 studies of adolescent ME/CFS patients. We assessed CBF using extracranial Doppler measurements of the internal carotid and vertebral arteries supine and during the tilt. We studied 42 adolescents during a 20 degree and 41 during a 70 degree test.

Results: At 20 degrees, no patients developed postural orthostatic tachycardia (POTS), compared to 32% at 70 degrees (p = 0.0002). The CBF reduction during the 20 degree tilt of -27(6)% was slightly less than during the reduction during a 70 degree test [-31(7)%; p = 0.003]. Seventeen adolescents had CBF measurements at both 20 and 70 degrees. The CBF reduction in these patients with both a 20 and 70 degrees test was significantly larger at 70 degrees than at 20 degrees (p < 0.0001).

Conclusions: A 20 degree tilt in young ME/CFS patients resulted in a CBF reduction comparable to that in adult patients during a 70 degree test. The lower tilt angle provoked less POTS, emphasizing the importance of using the 70 degree angle for that diagnosis. Further study is needed to explore whether CBF measurements during tilt provide an improved standard for classifying orthostatic intolerance.

Source: van Campen CLMC, Rowe PC, Visser FC. Comparison of a 20 degree and 70 degree tilt test in adolescent myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Front Pediatr. 2023 May 12;11:1169447. doi: 10.3389/fped.2023.1169447. PMID: 37252045; PMCID: PMC10213432. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10213432/ (Full text)