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)

Digital health app data reveals an effect of ovarian hormones on long COVID and myalgic encephalomyelitis symptoms

Abstract:

Background. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) disproportionately affect females, suggesting modulation by sex hormones. We sought to investigate whether symptom severity is influenced by changes in sex hormones over the menstrual cycle, or by hormonal contraception.

Methods: We carried out a retrospective analysis of menstrual and symptom data, prospectively collected via the Visible app from individuals with long COVID, ME/CFS, or both, who had regular menstrual cycles, between 7 September 2022 and 6 March 2024. Mixed-effects models were used to examine associations between symptom severity, menstrual cycle phase and contraception type.

Findings: 948 users were included; 100% of users were female and 92.6% identified as women. The most tracked symptoms were fatigue (99.5% of users), brain fog (88.3%), headaches (85.1%) and muscle aches (78.6%). All menstrual cycle phases showed a modest, but significant, improvement compare to the menstrual phase, most markedly in the early luteal (IRR 0.963%, 95% CI: 0.958 – 0.968), but also the follicular (IRR = 0.985, 95% CI: 0.981 – 0.990) and late luteal phase (IRR = 0.980, 95% CI: 0.974-0.985). Crashes (sudden and severe worsening of symptoms following exertion) were significantly more frequent during menstruation than in other phases. Users of combined hormonal contraception (n=70) had a statistically significant reduction in overall symptom score (OR = 0.827, 95% CI: 0.690 – 0.992) and crash incidence (OR = 0.548, 95% CI: 0.350 – 0.856) compared to those not using hormonal contraception (=786).

Interpretation: Menstruation is associated with worsened symptoms in long COVID and ME/CFS. Users of combined hormonal contraception report a lower symptom burden than non-users, suggesting a modulatory role of ovarian hormones. These findings could empower menstruating people living with long COVID and ME/CFS to anticipate cyclical changes in symptoms and plan their activities accordingly, and could also inform their use of contraception.

Source: Abigail Goodship, Rory Preston, Joseph T Hicks, Harry Leeming, Christian Morgenstern, Victoria Male. Digital health app data reveals an effect of ovarian hormones on long COVID and myalgic encephalomyelitis symptoms. medRxiv 2025.01.24.25321092; doi: https://doi.org/10.1101/2025.01.24.25321092 https://www.medrxiv.org/content/10.1101/2025.01.24.25321092v1 (Full text available as PDF file)

Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long COVID from controls

Abstract:

Background: Recent proteomic studies have documented that Long COVID in adults is characterized by a pro-inflammatory signature with thromboinflammation. However, if similar events happen also in children with Long COVID has never been investigated.

Methods: We performed an extensive protein analysis of blood plasma from pediatric patients younger than 19 years of age Long COVID and a control group of children with acute COVID-19, MIS-C, and healthy controls resulted similar for sex distribution and age. Children were classified as Long COVID if symptoms persisted for at least 8 weeks since the initial infection, negatively impacted daily life and could not be explained otherwise.

Results: 112 children were included in the study, including 34 children fulfilling clinical criteria of Long COVID, 32 acute SARS-CoV-2 infection, 27 MIS-C and 19 healthy controls. Compared with controls, pediatric Long COVID was characterized by higher expression of the proinflammatory and pro-angiogenetic set of chemokines CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a. A Machine Learning model based on proteomic profile was able to identify LC with an accuracy of 0.93, specificity of 0.86 and sensitivity of 0.97.

Conclusions: Pediatric Long COVID patients have a well distinct blood protein signature marked by increased ongoing general and endothelial inflammation, similarly as happens in adults.

Impact:

  • Pediatric Long COVID has a distinct blood protein signature marked by increased ongoing general and endothelial inflammation.
  • This is the first study studying and documenting proinflammatory profile in blood samples of children with long COVID.
  • Long COVID was characterized by higher expression of the proinflammatory and pro-angiogenetic set of chemokines CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a.
  • A proteomic profile was able to identify Long COVID with an accuracy of 0.93, specificity of 0.86 and sensitivity of 0.97.
  • These findings may inform development of future diagnostic tests.

Source: Buonsenso, D., Cotugno, N., Amodio, D. et al. Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long COVID from controls. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-03837-0  https://www.nature.com/articles/s41390-025-03837-0

Autoantibody-Driven Monocyte Dysfunction in Post-COVID Syndrome with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Post-COVID syndrome (PCS) has emerged as a significant health concern with persisting symptoms. A subset of PCS patients develops severe myalgic encephalomyelitis/chronic fatigue syndrome (pcME/CFS). Dysregulated autoantibodies (AABs) have been implicated in PCS, contributing to immune dysregulation, impairment of autonomous nerve and vascular function. As recently shown in autoimmune diseases, IgG fractions translate disease-specific pathways into various cells. Therefore, we asked whether IgG fractions from PCS patients could be applied in vitro to identify specific cytokine rersponses for PCS patients without (nPCS) and with pcME/CSF.

To assess this, we have stimulated monocyte cell lines with IgG fractions from PCS patients. Our findings reveal distinct patterns of immune regulation by AABs in vascular and immune dysfunction. In contrast to nPCS, pcME/CSF AABs induced enhanced neurotrophic responses, characterized by significant cytokine correlations involving brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and LIGHT. AAB-induced cytokine levels correlate with clinical symptoms. Further, this study emphasizes a contribution of AAB in PCS, in mitigating long-term immune dysregulation, and a need for therapies modulating IgG-induced pathways.

Source: Alexander HackelFranziska SotznyElise MennengaHarald HeideckeKai Schulze-FosterKontantinos FourlakisSusanne LuedersHanna GrasshoffKerstin RubarthFrank KonietschkeTanja LangeCarmen ScheibenbogenReza Akbarzade, Gabriela Riemekasten. Autoantibody-Driven Monocyte Dysfunction in Post-COVID Syndrome with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS

Abstract:

Autoreactive antibodies (AAB) are currently being investigated as causative or aggravating factors during post-COVID. In this study we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection. This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptors (ANSR) autoantibodies and neurological impairments.

We found that following immunoadsorption therapy, the ANSR autoantibodies were nearly eliminated from the patients’ blood. The removal of IgG antibodies was accompanied by a decrease of pro-inflammatory cytokines including IL4, IL2, IL1β, TNF and IL17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients.

30 days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a modest but statistically significant amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CFS questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.

Source: Anft M, Wiemers L, Rosiewicz KS, Doevelaar A, Skrzypczyk S, Kurek J, Kaliszczyk S, Seidel M, Stervbo U, Seibert FS, Westhoff TH, Babel N. Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS. Mol Ther. 2025 Jan 9:S1525-0016(25)00011-5. doi: 10.1016/j.ymthe.2025.01.007. Epub ahead of print. PMID: 39797400. https://www.cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016(25)00011-5.pdf (Full text) https://pubmed.ncbi.nlm.nih.gov/39797400/ (Abstract)

Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may occur after infection. How often people develop ME/CFS after SARS-CoV-2 infection is unknown.

Objective: To determine the incidence and prevalence of post-COVID-19 ME/CFS among adults enrolled in the Researching COVID to Enhance Recovery (RECOVER-Adult) study.

Design, setting, and participants: RECOVER-Adult is a longitudinal observational cohort study conducted across the U.S. We included participants who had a study visit at least 6 months after infection and had no pre-existing ME/CFS, grouped as (1) acute infected, enrolled within 30 days of infection or enrolled as uninfected who became infected (n=4515); (2) post-acute infected, enrolled greater than 30 days after infection (n=7270); and (3) uninfected (1439).

Measurements: Incidence rate and prevalence of post-COVID-19 ME/CFS based on the 2015 Institute of Medicine ME/CFS clinical diagnostic criteria.

Results: The incidence rate of ME/CFS in participants followed from time of SARS-CoV-2 infection was 2.66 (95% CI 2.63-2.70) per 100 person-years while the rate in matched uninfected participants was 0.93 (95% CI 0.91-10.95) per 100 person-years: a hazard ratio of 4.93 (95% CI 3.62-6.71). The proportion of all RECOVER-Adult participants that met criteria for ME/CFS following SARS-CoV-2 infection was 4.5% (531 of 11,785) compared to 0.6% (9 of 1439) in uninfected participants. Post-exertional malaise was the most common ME/CFS symptom in infected participants (24.0%, 2830 of 11,785). Most participants with post-COVID-19 ME/CFS also met RECOVER criteria for long COVID (88.7%, 471 of 531).

Limitations: The ME/CFS clinical diagnostic criteria uses self-reported symptoms. Symptoms can wax and wane.

Conclusion: ME/CFS is a diagnosable sequela that develops at an increased rate following SARS-CoV-2 infection. RECOVER provides an unprecedented opportunity to study post-COVID-19 ME/CFS.

Source: Vernon SD, Zheng T, Do H, Marconi VC, Jason LA, Singer NG, Natelson BH, Sherif ZA, Bonilla HF, Taylor E, Mullington JM, Ashktorab H, Laiyemo AO, Brim H, Patterson TF, Akintonwa TT, Sekar A, Peluso MJ, Maniar N, Bateman L, Horwitz LI, Hess R; NIH Researching COVID to Enhance Recovery (RECOVER) Consortium. Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study. J Gen Intern Med. 2025 Jan 13. doi: 10.1007/s11606-024-09290-9. Epub ahead of print. PMID: 39804551. https://link.springer.com/article/10.1007/s11606-024-09290-9 (Full text)

Cluster analysis to identify long COVID phenotypes using 129Xe magnetic resonance imaging: a multicentre evaluation

Abstract:

Background: Long COVID impacts ∼10% of people diagnosed with coronavirus disease 2019 (COVID-19), yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID. Therefore, we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes.

Methods: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129Xe MRI ∼14 months post-acute infection across three centres. Long COVID was defined as persistent dyspnoea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully recovered. 129Xe MRI ventilation defect percent (VDP) and membrane-to-gas (Mem/Gas), red blood cell-to-membrane (RBC/Mem) and red blood cell-to-gas (RBC/Gas) ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction.

Results: We evaluated 135 participants across three centres: 28 COVID-negative (mean±sd age 40±16 years), 34 fully recovered (42±14 years) and 73 long COVID (49±13 years). RBC/Mem (p=0.03) and forced expiratory volume in 1 s (FEV1) (p=0.04) were different between long COVID and COVID-negative; FEV1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster 1 was the youngest with normal MRI and mild gas trapping; Cluster 2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster 3 had mildly increased Mem/Gas with normal PFTs; and Cluster 4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern.

Conclusions: We identified four 129Xe MRI long COVID phenotypes with distinct characteristics. 129Xe MRI can dissect pathophysiological heterogeneity of long COVID to enable personalised patient care.

Source: Eddy RL, Mummy D, Zhang S, Dai H, Bechtel A, Schmidt A, Frizzell B, Gerayeli FV, Leipsic JA, Leung JM, Driehuys B, Que LG, Castro M, Sin DD, Niedbalski PJ. Cluster analysis to identify long COVID phenotypes using 129Xe magnetic resonance imaging: a multicentre evaluation. Eur Respir J. 2024 Mar 28;63(3):2302301. doi: 10.1183/13993003.02301-2023. PMID: 38331459; PMCID: PMC10973687. https://pmc.ncbi.nlm.nih.gov/articles/PMC10973687/ (Full text)