Journal of Clinical Medicine

Research

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12 pages, 396 KB

Open AccessArticle

Post-Exertional Malaise in Post-COVID-19 Syndrome: A Shift in the Frequency Across Pandemic Phases

by Alaa Ghali, Christian Lavigne, Maria Ghali and Valentin Lacombe

J. Clin. Med. 2026, 15(8), 2948; https://doi.org/10.3390/jcm15082948 - 13 Apr 2026

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Abstract

Background: Post-exertional malaise (PEM), which is the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is also reported in a proportion of patients with post-COVID-19 syndrome (PCS). Our objective was to identify determinants that may be linked to the emergence of PEM in [...] Read more.

Background: Post-exertional malaise (PEM), which is the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is also reported in a proportion of patients with post-COVID-19 syndrome (PCS). Our objective was to identify determinants that may be linked to the emergence of PEM in PCS patients. Methods: Patients fulfilling the World Health Organization definition for PCS who attended the post-COVID unit of the Internal Medicine Department of Angers University Hospital, France, between June 2020 and December 2023 were included retrospectively. Their medical records were reviewed to extract information on COVID-19 infection history, characteristics of post-exertional malaise (PEM), fatigue severity, and relevant epidemiological variables. Results: The study included 220 patients, grouped according to whether post-exertional malaise was present (PCS/PEM+) or absent (PCS/PEM–). PEM was observed in 26.4% of patients and was significantly linked to earlier COVID onset in 2020/2021 (OR 5.68 (95% CI: 1.66–19.45), p = 0.006), as well as higher fatigue levels (OR 2.07 (95% CI: 1.22–3.50), p = 0.007). Conclusions: Patients who contracted COVID-19 during the pre-Omicron period reported PEM more frequently than those infected in later waves. This observation could reflect differences in viral characteristics following the emergence of the Omicron variant; however, alternative explanations—such as increasing vaccination coverage, accumulating post-infectious immunity, or other unmeasured factors—cannot be ruled out. Based on the observed link between PEM and symptom severity, PCS patients should be systematically assessed for the presence of PEM. Full article

(This article belongs to the Special Issue POTS, ME/CFS and Long COVID: Recent Advances and Future Direction)

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11 pages, 218 KB

Open AccessArticle

Patient Characteristics of a Telemedicine Clinic for Pediatric and Young Adult Postural Orthostatic Tachycardia Syndrome

by Jeffrey R. Boris

J. Clin. Med. 2026, 15(4), 1626; https://doi.org/10.3390/jcm15041626 - 20 Feb 2026

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Abstract

Background: Postural orthostatic tachycardia syndrome (POTS) includes multiple symptoms and comorbid conditions. Assessment for less recognized symptoms and conditions was performed through a telemedicine-only clinic for adolescent and young adult patients with POTS. Methods: A retrospective review of records was performed [...] Read more.

Background: Postural orthostatic tachycardia syndrome (POTS) includes multiple symptoms and comorbid conditions. Assessment for less recognized symptoms and conditions was performed through a telemedicine-only clinic for adolescent and young adult patients with POTS. Methods: A retrospective review of records was performed for information obtained during clinical care. Patients up through the age of 23 years were evaluated, either diagnosing or confirming a diagnosis of POTS, and identifying other symptoms and diagnoses. These data were evaluated for differences, including by sex and presence or absence of joint hypermobility. Results: In total, 277 patients met the inclusion criteria. The median age was 16.8 years (IQR 15.2–19.1); 88.1% were female. Suspected mast cell activation syndrome occurred in 70% of patients. Joint hypermobility was found in 78.3% of patients; female patients were more affected (80.3% versus 63.6%); 57.0% had both suspected MCAS and joint hypermobility. Migraine was seen in 51.6% of patients; 57.4% had tension-type headache. Females appeared more likely to have tension headache or both types of headache together, while males seemed more likely to have migraine. Joint hypermobility did not influence headache presence or absence. A history of head trauma/concussion was reported in 39.7% of patients, with 14.4% having vestibular symptoms and 4% having convergence disorder. Without head trauma/concussion, 23.8% of patients reported vestibular symptoms, convergence disorder, or both. Conclusions: We report previously unrecognized or poorly described symptoms and conditions accompanying POTS. Recognition of these symptoms and conditions in patients with POTS can allow for more complete evaluation and management of debilitating factors and may give insights into underlying pathophysiologies leading to POTS. Full article

(This article belongs to the Special Issue POTS, ME/CFS and Long COVID: Recent Advances and Future Direction)

23 pages, 1461 KB

Open AccessArticle

Impact of Pulmonary Rehabilitation on Physical, Mental Health and Quality of Life in Children with Post-COVID-19 Condition: A 12-Month Quasi-Experimental Study

by Aroia Goicoechea-Calvo, Natalia Navarro Expósito, Roser Coll-Fernández, Marc Colomer Giralt, Alberto Martín Saavedra, Alba González-Aumatell, María Méndez-Hernández, Clara Carreras-Abad, Mónica Moreira, Maria Giralt-López, Natàlia Pallarès, Cristian Tebe Cordomi, Agustí Rodríguez-Palmero, Carlos Rodrigo and Maria José Durà Mata

J. Clin. Med. 2026, 15(2), 535; https://doi.org/10.3390/jcm15020535 - 9 Jan 2026

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Abstract

Background/Objectives: Evidence on pulmonary rehabilitation (PR) in paediatric post-COVID-19 condition (PPCC) is scarce. This study aimed to evaluate the association of a PR programme with changes in physical and mental health and quality of life in PPCC over a 12-month follow-up. Methods: A [...] Read more.

Background/Objectives: Evidence on pulmonary rehabilitation (PR) in paediatric post-COVID-19 condition (PPCC) is scarce. This study aimed to evaluate the association of a PR programme with changes in physical and mental health and quality of life in PPCC over a 12-month follow-up. Methods: A quasi-experimental pre–post single-arm study was conducted, with no control group, in PPCC patients attending an outpatient PR unit. The primary outcome was change in exercise capacity (6 min walk test, 6MWT). Secondary outcomes included inspiratory and peripheral muscle strength, quadriceps muscle morphology by ultrasound, fatigue, physical activity, quality of life, and psychiatric symptoms, assessed using validated paediatric instruments. Results: A total of 115 PPCC patients (mean age 13.3 years; 66.1% female) completed the PR. 6MWD distance increased from 509 ± 87 to 546 ± 86 (+37 m; p < 0.001; D: 0.50). Handgrip strength increased by 2.4 kg, maximal inspiratory pressure increased by 15 cmH₂O, physical activity increased by 2.4 points, fatigue score improved by 9.3 points, and quality of life improved by 11 points (all p < 0.001). Rectus femoris thickness increased by 0.56 mm (p = 0.005), psychiatric symptom scores decreased by 4.5 points (p < 0.001), and rectus femoris echo-intensity decreased (p = 0.003). Conclusions: Multidisciplinary PR appears feasible and potentially effective in improving physical function, psychological well-being, and quality of life in PPCC, supporting the need for evidence-based paediatric rehabilitation. Full article

(This article belongs to the Special Issue POTS, ME/CFS and Long COVID: Recent Advances and Future Direction)

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15 pages, 497 KB

Open AccessArticle

Autonomic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Findings from the Multi-Site Clinical Assessment of ME/CFS (MCAM) Study in the USA

by Anindita Issa, Jin-Mann S. Lin, Yang Chen, Jacob Attell, Dana Brimmer, Jeanne Bertolli, Benjamin H. Natelson, Charles W. Lapp, Richard N. Podell, Andreas M. Kogelnik, Nancy G. Klimas, Daniel L. Peterson, Lucinda Bateman and Elizabeth R. Unger

J. Clin. Med. 2025, 14(17), 6269; https://doi.org/10.3390/jcm14176269 - 5 Sep 2025

Cited by 3 | Viewed by 10534

Abstract

Background/Objectives: Symptoms of autonomic dysfunction are common in infection-associated chronic conditions and illnesses (IACCIs), including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to evaluate autonomic symptoms and their impact on ME/CFS illness severity. Methods: Data came from a multi-site study [...] Read more.

Background/Objectives: Symptoms of autonomic dysfunction are common in infection-associated chronic conditions and illnesses (IACCIs), including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to evaluate autonomic symptoms and their impact on ME/CFS illness severity. Methods: Data came from a multi-site study conducted in seven ME/CFS specialty clinics during 2012–2020. Autonomic dysfunction was assessed using the Composite Autonomic Symptom Scale 31 (COMPASS-31), medical history, and a lean test originally described by the National Aeronautics and Space Administration (NASA). Illness severity was assessed using Patient-Reported Outcomes Measurement Information System measures, the 36-item short-form, as well as the CDC Symptom Inventory. This analysis included 442 participants who completed the baseline COMPASS-31 assessment, comprising 301 individuals with ME/CFS and 141 healthy controls (HC). Results: ME/CFS participants reported higher autonomic symptom burden than HC across three assessment tools (all p < 0.0001), including the COMPASS-31 total score (34.1 vs. 6.8) and medical history indicators [dizziness or vertigo (42.6% vs. 2.8%), cold extremities (38.6% vs. 5.7%), and orthostatic intolerance (OI, 33.9% vs. 0.7%)]. Among ME/CFS participants, 97% had at least one autonomic symptom. Those with symptoms in the OI, gastrointestinal, and pupillomotor domains had significantly higher illness severity than those without these symptoms. Conclusions: ME/CFS patients exhibit a substantial autonomic symptom burden that correlates with greater illness severity. Individualized care strategies targeting dysautonomia assessment and intervention may offer meaningful improvements in symptom management and quality of life for those with ME/CFS and similar chronic conditions. Full article

(This article belongs to the Special Issue POTS, ME/CFS and Long COVID: Recent Advances and Future Direction)

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Review

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13 pages, 248 KB

Open AccessReview

Postural Orthostatic Tachycardia Syndrome, Menopause and Hormone Replacement Therapy: Clinical Decisions in Times of Uncertainty

by Svetlana Blitshteyn

J. Clin. Med. 2026, 15(4), 1477; https://doi.org/10.3390/jcm15041477 - 13 Feb 2026

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Abstract

Postural orthostatic tachycardia syndrome (POTS), characterized by a rise in heart rate of at least 30 beats per minute from supine to standing position without accompanying orthostatic hypotension, is one of the most common autonomic disorders with disabling cardiovascular and neurologic manifestations. Hormonal [...] Read more.

Postural orthostatic tachycardia syndrome (POTS), characterized by a rise in heart rate of at least 30 beats per minute from supine to standing position without accompanying orthostatic hypotension, is one of the most common autonomic disorders with disabling cardiovascular and neurologic manifestations. Hormonal influence has been long recognized by the disorder predominantly affecting women of reproductive age, with frequent onset around menarche, exacerbation of symptoms before or during menses, and pregnancy being one of POTS triggers. Hormone replacement therapy (HRT) and menopause in women with POTS have not been studied, but issues surrounding HRT are highly relevant as women with POTS transition from reproductive age to menopause. Given a rising prevalence of POTS due to post-COVID onset and the US Food and Drug Administration recently removing the black box warning on estrogen-containing HRT formulations, informed decisions and risk assessments regarding HRT use in women with POTS are warranted. In this narrative review, existing studies on hormones and POTS and its common comorbidities are reviewed, and key points in decision-making on the use of HRT in women with POTS are discussed. In summary, for women with significant menopausal symptoms and/or exacerbation of POTS during the peri- or postmenopausal period, using some forms of HRT for treatment of menopausal symptoms may be considered, accounting for comorbidities, cardiovascular risk and other factors. Vaginal estrogen appears to be safe for most women while transdermal estrogen and micronized progesterone can be utilized for significant menopausal symptoms, although outcomes of their long-term use are unknown. Full article

(This article belongs to the Special Issue POTS, ME/CFS and Long COVID: Recent Advances and Future Direction)

43 pages, 595 KB

Open AccessReview

An Overview of Severe Myalgic Encephalomyelitis

by Mark Vink and Alexandra Vink-Niese

J. Clin. Med. 2026, 15(2), 805; https://doi.org/10.3390/jcm15020805 - 19 Jan 2026

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Abstract

In this article, we have reviewed the literature on severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a clinical diagnosis in the absence of a diagnostic test. However, in research settings and disability disputes, 2-day cardiopulmonary exercise testing can be used to diagnose [...] Read more.

In this article, we have reviewed the literature on severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a clinical diagnosis in the absence of a diagnostic test. However, in research settings and disability disputes, 2-day cardiopulmonary exercise testing can be used to diagnose and document the abnormal response to exercise. Biomedical research into this disease has been scarce and underfunded for decades. Consequently, there are no effective treatments. In its most severe form, it is more disabling than many other diseases, and patients are bedbound 24/7, dependent on carers, and spend their days in dark and quiet rooms. Even the soft sound of a human voice can lead to further deterioration. Some of the very severely ill suffer from life-threatening malnutrition and need to be tube-fed. The COVID-19 pandemic has led to a sharp increase in the number of patients with post-infectious diseases, and many of them fulfill ME/CFS criteria. Dedicated, focused research using advanced medical technologies is needed to gain further understanding of the underlying disease mechanism. This will enable us to find effective pharmacological treatments and address the unmet medical needs of these very ill people. Full article

(This article belongs to the Special Issue POTS, ME/CFS and Long COVID: Recent Advances and Future Direction)

Other

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16 pages, 752 KB

Open AccessProject Report

Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID

by Julia Barr, Lowri Marsden, Theshan Dassanayake, Norah Almutairi, Vikki McKeever, Tarek Gaber, Rachel Tarrant, Belinda Godfrey, Sharon Witton and Manoj Sivan

J. Clin. Med. 2026, 15(7), 2510; https://doi.org/10.3390/jcm15072510 - 25 Mar 2026

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Abstract

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are complex multisystem conditions with significant functional disability. Many patients experience symptoms of orthostatic intolerance, which can be captured in some cases as Orthostatic Hypotension (OH) or Postural orthostatic Tachycardia Syndrome (PoTS) [...] Read more.

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are complex multisystem conditions with significant functional disability. Many patients experience symptoms of orthostatic intolerance, which can be captured in some cases as Orthostatic Hypotension (OH) or Postural orthostatic Tachycardia Syndrome (PoTS) on objective testing. Conservative treatments are recommended for first-line symptom management, but there is a lack of efficacy evidence. This study aims to assess the feasibility of an 8-week clinically supervised, personalised Dysautonomia Management Protocol (DMP) in a cohort of ME/CFS and LC patients with subjective and objective evidence of orthostatic intolerance (dysautonomia). Methods: ME/CFS and LC patients with objective dysautonomia on the 10 min active Lean Test (LT) were recruited to an 8-week DMP, with interventions introduced cumulatively every two weeks. Interventions included increasing daily fluid intake to 3 litres and salt intake to 10 g, pacing to avoid crashes and calf activation. Baseline and weekly data collection included the LT, Composite Autonomic Symptom Score questionnaire (COMPASS-31) and Yorkshire Rehabilitation Scale (YRS). Results: Sixteen participants completed the 8-week program, five discontinued during the program, and one was withdrawn following a severe crash. The COMPASS-31 improved by 7.7 points from week 1 to week 8 (p = 0.045), with a medium Cohen’s d effect size of 0.55. For the same period, there was a non-significant (p = 0.16) improvement in the YRS symptom severity score by 2 points. Comparing the final two weeks of the program with the first two weeks, mean heart rate during the LT decreased by 4.8 beats per minute (p = 0.032), with a medium Cohen’s d effect size of 0.44. Adherence to the interventions was highly variable, with none of the patients able to fully employ all four recommendations. Conclusions: The results suggest that targeted conservative interventions could influence autonomic function and symptom reduction. However, the magnitude of change was limited, and statistical significance might not necessarily relate to a clinically significant improvement in symptoms. Full article

(This article belongs to the Special Issue POTS, ME/CFS and Long COVID: Recent Advances and Future Direction)

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7 pages, 404 KB

Open AccessBrief Report

A Signal for Voice and Speech Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

by Stephanie L. Grach, Jaime Seltzer and Diana M. Orbelo

J. Clin. Med. 2025, 14(14), 4847; https://doi.org/10.3390/jcm14144847 - 8 Jul 2025

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Abstract

Background/Objectives: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may report abnormalities in voice and speech; however, no formal research has been conducted in this area. Methods: An online mixed-methods survey was completed by 685 people with ME/CFS. A total of 302 [...] Read more.

Background/Objectives: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may report abnormalities in voice and speech; however, no formal research has been conducted in this area. Methods: An online mixed-methods survey was completed by 685 people with ME/CFS. A total of 302 respondents completed the qualitative component (44.09%). Questions assessed disease experience with ME/CFS and post-exertional malaise without prompting on specific symptoms. Within the qualitative results, a search of the terms “speech, voice,” “words,” and “speak” was conducted. Results: Excluding neurocognitive associations, colloquial phrases, and “speech therapy,” there were 38 mentions of the terms in the context of voice or speech changes across 28 unique qualitative survey responses (9.27%). Conclusions: A notable portion of respondents reported voice or speech changes when responding to open-ended qualitative questions about their disease experience. More research is needed regarding the implications of voice and speech anomalies in ME/CFS pathology and disease monitoring. Full article

(This article belongs to the Special Issue POTS, ME/CFS and Long COVID: Recent Advances and Future Direction)

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