Category: Overlapping Illnesses

Serum Spike Protein Persistence Post COVID Is Not Associated with ME/CFS

Abstract:

Background/Objectives: According to the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), an estimated 3-6% of people suffer from post-COVID condition or syndrome (PCS). A subset meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies have reported that SARS-CoV-2 proteins or RNA can persist after acute infection in serum or tissues, but their role in PCS is unclear.

Methods: Here, SARS-CoV-2 spike protein was analyzed in the serum of 121 PCS patients with predominant fatigue and exertional intolerance, of whom 72 met diagnostic criteria for ME/CFS, 37 post-COVID recovered healthy controls, and 32 pre-pandemic healthy controls.

Results: Spike protein was detected in the serum of 11% of recovered controls, 2% of PCS patients, and 14% of ME/CFS patients between 4 and 31 months after SARS-CoV-2 infection, but not in pre-pandemic samples. The occurrence and concentration of spike protein did not correlate with infection or vaccination timepoints. In ME/CFS patients, spike protein presence was not associated with the severity of symptoms or functional disability. In 5 out of 22 patients who under-went immunoglobulin depletion, spike protein levels were reduced or undetectable after treatment, indicating binding to immunoglobulins.

Conclusions: In summary, this study identified serum spike protein in a subset of patients but found no association with ME/CFS.

Source: Fehrer A, Sotzny F, Kim L, Kedor C, Freitag H, Heindrich C, Grabowski P, Babel N, Scheibenbogen C, Wittke K. Serum Spike Protein Persistence Post COVID Is Not Associated with ME/CFS. J Clin Med. 2025 Feb 8;14(4):1086. doi: 10.3390/jcm14041086. PMID: 40004616. https://www.mdpi.com/2077-0383/14/4/1086 (Full text)

Comparative Study Between Cognitive Phenotypes of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Multiple Sclerosis

Abstract:

Objective: Cognitive impairments are one of the most common and disabling symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here, we address the possibility of a specific cognitive profile inherent to ME/CFS. Due to the occurrence of cognitive deficits, fatigue, and pain in both pathologies, multiple sclerosis (MS) is a relevant comparison model. For this purpose, we carried out a comparative study between cognitive profiles of patients with ME/CFS and patients suffering from MS.

Methods: In total, 40 ME/CFS and 40 MS patients were included. A complete screening of all cognitive functions was carried out through an extensive battery of tests routinely used in clinical practice.

Results: ME/CFS and MS patients showed deficits in episodic memory retrieval, visual selective attention and reading speed. ME/CFS patients also elicited a lower level of performance than MS patients regarding consolidation. For both groups, levels of performance on these cognitive tests did not correlate with levels of fatigue, pain, and depression.

Conclusions: This study highlighted both similarities and differences in the cognitive profiles of ME/CFS and MS patients. While both groups exhibited deficits in episodic memory retrieval, visual selective attention, and reading speed, ME/CFS patients showed distinct impairment in consolidation processes. These cognitive deficits were not correlated with fatigue, pain, or depression, reinforcing the hypothesis of intrinsic cognitive dysfunction in ME/CFS. These findings define a specific cognitive phenotype for ME/CFS, which could improve diagnostic accuracy and therapeutic strategies. Future research, particularly in functional imaging, may elucidate the neurobiological mechanisms underlying these impairments.

Source: Aoun Sebaiti M, Oubaya N, Gounden Y, Samson C, Lechapt E, Wahab A, Creange A, Hainselin M, Authier FJ. Comparative Study Between Cognitive Phenotypes of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Multiple Sclerosis. Diagnostics (Basel). 2025 Feb 17;15(4):487. doi: 10.3390/diagnostics15040487. PMID: 40002638. https://www.mdpi.com/2075-4418/15/4/487 (Full text)

A comparison of genome-wide association analyses of persistent symptoms after Lyme disease, fibromyalgia, and myalgic encephalomyelitis – chronic fatigue syndrome

Abstract:

Background: Up to 20% of Lyme disease cases experience post-treatment Lyme disease syndrome (PTLDS). The biological basis for PTLDS is poorly understood and no evidence-based treatment has been identified. Genetic studies have the potential to elucidate PTLDS pathophysiology and identify treatment targets.

Methods: We used electronic health record data (EHR) and genetic data from a linked biorepository to conduct a genome-wide association study (GWAS) for PTLDS among patients from a Pennsylvania health system. We evaluated the validity of the GWAS results in two separate conditions that have hypothesized overlapping pathophysiology, fibromyalgia and myalgic encephalomyelitis – chronic fatigue syndrome (ME/CFS). GWAS analyses were performed using logistic regression in SUGEN, assuming an additive genetic model, and adjusting for age, sex, array, and the first 10 principal components calculated from whole genome genotyping to adjust for ancestry, and accounting for relatedness including all 1st degree relationships. The functional mapping and annotation analysis (FUMA) tool was used to explore top findings from our GWAS.

Results: Among the 161,875 eligible MyCode participants with genotyping, there were 3,585 who met the criteria for treated Lyme disease. A subset of 695 (19.4%) of these patients met the criteria for PTLDS and the remaining 2890 were classified as controls. We identified two PTLDS loci that reached the suggestive significance threshold (P < 5 × 10– 7), with lead variants rs77857587, near IRX1, and rs10833979, near GAS2. Our top index single nucleotide polymorphism (SNP), rs77857587, is in high linkage disequilibrium with a long-range protein quantitative locus SNP, rs111774530, for the MARC2 (Mitochondrial Amidoxime Reducing Component 2) protein. We identified 5,041 cases of fibromyalgia (150,599 controls) and 2,268 cases of ME/CFS (151,594 controls) among the MyCode participants. Neither of the two suggestively significant loci were associated with fibromyalgia or ME/CFS.

Conclusion: We identified two PTLDS loci that reached a suggestive significance threshold. Our top index SNP is associated with the MARC2 protein, a protein that has been linked to multiple immune checkpoints. Further study is needed in a larger population to evaluate whether there is genetic evidence of the role of immune response in the occurrence of PTLDS.

Source: Hirsch AG, Justice AE, Poissant A, Nordberg CM, Josyula NS, Aucott J, Rebman AW, Schwartz BS. A comparison of genome-wide association analyses of persistent symptoms after Lyme disease, fibromyalgia, and myalgic encephalomyelitis – chronic fatigue syndrome. BMC Infect Dis. 2025 Feb 24;25(1):265. doi: 10.1186/s12879-024-10238-x. PMID: 39994562; PMCID: PMC11853495. https://pmc.ncbi.nlm.nih.gov/articles/PMC11853495/ (Full text)

Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination

Summary:

COVID-19 vaccines have prevented millions of COVID-19 deaths. Yet, a small fraction of the population reports a chronic debilitating condition after COVID-19 vaccination, often referred to as post-vaccination syndrome (PVS). To explore potential pathobiological features associated with PVS, we conducted a decentralized, cross-sectional study involving 42 PVS participants and 22 healthy controls enrolled in the Yale LISTEN study.

Compared with controls, PVS participants exhibited differences in immune profiles, including reduced circulating memory and effector CD4 T cells (type 1 and type 2) and an increase in TNFα+ CD8 T cells. PVS participants also had lower anti-spike antibody titers, primarily due to fewer vaccine doses. Serological evidence of recent Epstein-Barr virus (EBV) reactivation was observed more frequently in PVS participants. Further, individuals with PVS exhibited elevated levels of circulating spike protein compared to healthy controls.

These findings reveal potential immune differences in individuals with PVS that merit further investigation to better understand this condition and inform future research into diagnostic and therapeutic approaches.

Source: Bornali Bhattacharjee, Peiwen Lu, Valter Silva Monteiro, Alexandra Tabachnikova, Kexin Wang, William B. Hooper, Victoria Bastos, Kerrie Greene, Mitsuaki Sawano, Christian Guirgis, Tiffany J. Tzeng, Frederick Warner, Pavlina Baevova, Kathy Kamath, Jack Reifert, Danice Hertz, Brianne Dressen, Laura Tabacof, Jamie Wood, Lily Cooke, Mackenzie Doerstling, Shadan Nolasco, Amer Ahmed, Amy Proal, David Putrino, Leying Guan, Harlan M. Krumholz, Akiko Iwasaki. Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination medRxiv 2025.02.18.25322379; doi: https://doi.org/10.1101/2025.02.18.25322379 https://www.medrxiv.org/content/10.1101/2025.02.18.25322379v1.full-text (Full text)

Language Matters: What Not to Say to Patients with Long COVID, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Other Complex Chronic Disorders

Abstract:

People with Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic disorders consistently report having difficulty obtaining effective and compassionate medical care and being disbelieved, judged, gaslighted, and even dismissed by healthcare professionals. We believe that these adversarial interactions and language are more likely to arise when healthcare professionals are confronting complex chronic illnesses without proper training, diagnostic biomarkers, or FDA-approved therapies.
These problematic conversations between practitioners and patients often involve specific words and phrases—termed the “never-words”—can leave patients in significant emotional distress and negatively impact the clinician–patient relationship and recovery. Seeking to prevent these destructive interactions, we review key literature on best practices for difficult clinical conversations and discuss the application of these practices for people with Long COVID, ME/CFS, dysautonomia, and other complex chronic disorders. We provide recommendations for alternative, preferred phrasing to the never-words, which can enhance therapeutic relationship and chronic illness patient care via compassionate, encouraging, and non-judgmental language.
Source: Smyth NJ, Blitshteyn S. Language Matters: What Not to Say to Patients with Long COVID, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Other Complex Chronic Disorders. International Journal of Environmental Research and Public Health. 2025; 22(2):275. https://doi.org/10.3390/ijerph22020275 https://www.mdpi.com/1660-4601/22/2/275 (Full text)

Post-COVID-19 Small Fiber Neuropathy as a New Emerging Quality of Life-Threatening Disease: A Systematic Review

Abstract:

Post-acute sequelae of COVID-19 (PASC) syndrome is considered an emergent and diffuse multidisciplinary problem. Compelling evidence suggests that COVID-19 increases symptoms of pre-existent small fiber neuropathy (SFN) and might trigger de novo onset of SFN. In this systematic review, for the first time, we provide a comprehensive overview of the clinical and diagnostic features of PASC-SFN, including the accompanying disorders, disease evolution, and possible treatments, described in the recent literature.
Following infection, many patients reported a wide range of symptoms and complications, not self-limiting and independent from previous infection severity. SFN begins more frequently with distal limb burning pain and numbness, which accompany other dysautonomia, cognitive, visual, and osteoarticular disorders involving multiple organ systems. In an initial diagnostic suspicion, some tests might be useful as complementary examinations, such as nerve quantitative sensory testing, electromyography, and optic nerve tomography. Otherwise, definite diagnosis is reached with skin biopsy as the gold standard, along with corneal in vivo microscopy when ocular discomfort is present.
Being a long-term condition, multiple and dissimilar symptomatic and disease-modifying drugs were employed for the treatment of this condition with the achievement of partial results, including steroids, pregabalin, gabapentin, duloxetine, vitamins, homotaurine and phosphatidylserine, alpha lipoic acid, immunosuppressants, and intravenous immunoglobulin therapy. PASC-SFN is a complex emerging disease and extremely challenging for physicians. At present, the only feasible management of PASC-SFN is represented by a multidisciplinary tailored approach, with future definitive protocols for diagnosis and treatment deemed essential.
Source: Bandinelli F, Di Carlo M, Colantuono VA, Nozzoli F, Salaffi F, Chiocchetti B, Nucci E, Mastricci A, Gherardi E, Manetti M. Post-COVID-19 Small Fiber Neuropathy as a New Emerging Quality of Life-Threatening Disease: A Systematic Review. Microorganisms. 2025; 13(2):328. https://doi.org/10.3390/microorganisms13020328 https://www.mdpi.com/2076-2607/13/2/328 (Full text)

Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID

Abstract:

Background: Long-COVID is defined as the persistency or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. Common persistent symptoms are fatigue, sleep disturbances, post-exertional malaise (PEM), pain, and cognitive problems. Long-COVID is estimated to be present in about 65 million people. We aimed to explore clinical and biological factors that might contribute to Long-COVID.

Methods: Prospective longitudinal cohort study including patients infected with SARS-CoV-2 between March 2020 and March 2022. Patients were assessed between 4 and 12 months after infection at the COVID follow-up clinic at UZ Leuven. We performed a comprehensive clinical assessment (including questionnaires and the 6-min walking test) and biological measures (global DNA methylation, telomere length, mitochondrial DNA copy number, inflammatory cytokines, and serological markers such as C-reactive protein, D-dimer, troponin T).

Results: Of the 358 participants, 328 were hospitalised, of which 130 had severe symptoms requiring intensive care admission; 30 patients were ambulatory referrals. Based on their clinical presentation, we could identify 6 main clusters. One-hundred and twenty-seven patients (35.4%) belonged to at least one cluster. The bigger cluster included PEM, fatigue, sleep disturbances, and pain (n = 57). Troponin T and telomere shortening were the two main markers predicting Long-COVID and PEM-fatigue symptoms.

Conclusions: Long-COVID is not just one entity. Different clinical presentations can be identified. Cardiac involvement (as measured by troponin T levels) and telomere shortening might be a relevant risk factor for developing PEM-fatigue symptoms and deserve further exploring.

Source: Polli A, Godderis L, Martens DS, Patil MS, Hendrix J, Wyns A, Van Campenhout J, Richter E, Fanning L, Vandekerckhove O, Claeys E, Janssens W, Lorent N. Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID. BMC Med. 2025 Feb 4;23(1):60. doi: 10.1186/s12916-025-03881-x. PMID: 39901177; PMCID: PMC11792217. https://pmc.ncbi.nlm.nih.gov/articles/PMC11792217/ (Full text)

Cerebral Blood Flow in Orthostatic Intolerance

Abstract:

Cerebral blood flow (CBF) is vital for delivering oxygen and nutrients to the brain. Many forms of orthostatic intolerance (OI) involve impaired regulation of CBF in the upright posture, which results in disabling symptoms that decrease quality of life. Because CBF is not easy to measure, rises in heart rate or drops in blood pressure are used as proxies for abnormal CBF. These result in diagnoses such as postural orthostatic tachycardia syndrome and orthostatic hypotension. However, in many other OI syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and long COVID, heart rate and blood pressure are frequently normal despite significant drops in CBF. This often leads to the incorrect conclusion that there is nothing hemodynamically abnormal in these patients and thus no explanation or treatment is needed. There is a need to measure CBF, as orthostatic hypoperfusion is the shared pathophysiology for all forms of OI. In this review, we examine the literature studying CBF dysfunction in various syndromes with OI and evaluate methods of measuring CBF including transcranial Doppler ultrasound, extracranial cerebral blood flow ultrasound, near infrared spectroscopy, and wearable devices.

Source: Khan MS, Miller AJ, Ejaz A, Molinger J, Goyal P, MacLeod DB, Swavely A, Wilson E, Pergola M, Tandri H, Mills CF, Raj SR, Fudim M. Cerebral Blood Flow in Orthostatic Intolerance. J Am Heart Assoc. 2025 Feb 3:e036752. doi: 10.1161/JAHA.124.036752. Epub ahead of print. PMID: 39895557. https://www.ahajournals.org/doi/10.1161/JAHA.124.036752 (Full text)

Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome

Abstract:

Background: Etiology remains elusive for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and no treatment exists. Antivirals had no efficacy in randomized clinical trials (RCT) for Epstein-Barr Virus and HHV-6. Enteroviruses (EV) have been implicated, but no antivirals are available. Many patients who received SARS–CoV-2-specific antiviral drugs for acute Covid-19 (COV19) infection experienced significant improvement of prior ME/CFS symptoms. This study summarizes their responses to antivirals for SARS-Cov-2.
Methods: Neutralizing Antibody (NA) for Coxsackievirus B (CVB)1-6 and Echovirus 6, 7, 9, 11, 30 were done by ARUP lab. Enterovirus Protein (EVP) of Peripheral Blood Leukocytes (PBL) was determined by Western Blot. ME/CFS patients fulfilled Canadian consensus criteria, and had either elevated NA for enteroviruses and/or positive EVP in PBL. ME/CFS patients hospitalized for acute COV19 infection and patients without COV19, were given 5-10 days of IV Remdesivir (Rem) +/- immune modulators. Controls: 20 ME/CFS patients seen concurrently without Remdesivir treatment. Other ME/CFS patients (non-COV19) were given Nirmaltrelvir/Ritonavir (PAX) daily for 10 days +/- one repeat. The energy index (EI) was monitored by the patients before, during and after treatment. Significant improvement was defined as > 30%.
Results: 15/20 (75%) ME/CFS patients – 10/12 hospitalized, 5/8 non-COV19 patients – responded to IV Rem 2-6 weeks after infusions; remission lasted 6-8 weeks to 6-9 months before relapse. Of Controls: 2/20 had mild improvement (< 0.001, X 2 ).

104/200 (52%) of PAX-treated ME/CFS patients improved, often within 2-3 days; all relapsed within days to weeks after treatment. 66%, 33% and 44% of CVB4+, CVB3+, non-CVB3,4+ patients responded to treatment, respectively. EVP decreased and increased with clinical response and relapse.

Conclusion: Rem and PAX demonstrated clinical efficacy in ME/CFS patients with chronic enterovirus infections. Placebo-controlled RCT will be needed to clarify the role of antivirals in ME/CFS.
Source: John K Chia, David Wang, P-2363. Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome, Open Forum Infectious Diseases, Volume 12, Issue Supplement_1, February 2025, ofae631.2514, https://doi.org/10.1093/ofid/ofae631.2514 https://academic.oup.com/ofid/article/12/Supplement_1/ofae631.2514/7988721?login=false 

Small fiber neuropathy in the post-COVID condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical significance and diagnostic challenges

Abstract:

Background: Patients with post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience symptoms potentially associated with small fiber neuropathy (SFN).

Methods: A sample of 90 participants, comprising 30 PCC patients, 30 ME/CFS patients, and 30 healthy controls (HC), matched by sex and age, was assessed. Neuropathic, autonomic, and fatigue symptoms were measured with TaskForce Monitor, the Sudoscan, heat and cold evoked potentials, In Vivo Corneal Confocal Microscopy (IVCCM), and specialized questionaries.

Results: PCC and ME/CFS patients demonstrated significantly higher levels of autonomic symptoms (H = 39.89, p < 0.001), neuropathic symptoms (H = 48.94, p < 0.001), and fatigue (H = 49.29, p < 0.001) compared to HC. Quantitative sensory testing revealed significant differences in heat detection thresholds between PCC patients and HC (F = 4.82; p < 0.01). Regarding corneal small fiber tortuosity, there were statistically significant differences between patients and HC (F = 6.80; p < 0.01), indicating pathological responses in patients. Small fiber tortuosity in IVCCM was identified as the main discriminator between patients and HC (AUC = 0.720; p < 0.01).

Conclusion: PCC and ME/CFS patients demonstrated sensory SFN, as evidenced by impaired heat detection and increased tortuosity of small fibers in the central corneal subbasal plexus. The findings underscore the importance of a multimodal approach to comprehensively detect and characterize SFN. This study provides valuable scientific insights into the neuropathic manifestations associated with these conditions.

Source: Azcue N, Teijeira-Portas S, Tijero-Merino B, Acera M, Fernández-Valle T, Ayala U, Barrenechea M, Murueta-Goyena A, Lafuente JV, de Munain AL, Ruiz-Irastorza G, Martín-Iglesias D, Gabilondo I, Gómez-Esteban JC, Del Pino R. Small fiber neuropathy in the post-COVID condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical significance and diagnostic challenges. Eur J Neurol. 2025 Feb;32(2):e70016. doi: 10.1111/ene.70016. PMID: 39888240. https://onlinelibrary.wiley.com/doi/10.1111/ene.70016 (Full text)