Myopathy as a cause of Long COVID fatigue: Evidence from quantitative and single fiber EMG and muscle histopathology

Engell-Sørensen, Thomas; Hejbøl, Eva Kildall; Blicher, Jakob Udby; Pedersen, Thomas Klit; Pedersen, Anders Lehmann Dahl; Hvass, Andreas Fløe; Khan, Benjamin Yamin Ali; Schiøttz-Christensen, Berit; Cömert, Cagla; Laustsen, Christoffer; Bendstrup, Elisabeth; Wood, Grégory; Bøtker, Hans Erik; Tankisi, Hatice; Andersen, Henning; Agergaard, Jane; Palmfeldt, Johan; Skaalum, Kristoffer; Østergaard, Lars; Vibholm, Line K.; Mølhave, Martin; Olsen, Rikke Katrine Jentoft; Jørgensen, Sofie E.; Poulsen, Steen Hvitfeldt; Leth, Steffen; Haugen, Søren Sperling; Harbo, Thomas; Mogensen, Trine H.; Kim, Wonyong

doi:10.1016/j.clinph.2023.01.010

Cited by 8 publications

(10 citation statements)

References 30 publications

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“…Another study investigating metabolism rates of the brain among long COVID patients found hypometabolism in regions associated with disturbed smell, cognitive impairment, pain, and insomnia (Guedj et al, 2021). Notably, in the context of documented cases of neuromuscular pathology, with indications of abnormal transmission at the neuromuscular junctions among long COVID patients, the observation of a link between acute headaches and subsequent neurological symptoms adds an interesting dimension to our ndings (Agergaard, Yamin Ali Khan, et al, 2023). Recent research has also demonstrated that various SARS-CoV-2 variants exhibit neuroinvasive capabilities by utilizing the olfactory pathway while also inciting localized in ammation in nervous tissues.…”

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confidence: 53%

“…However, these ndings in the CSF are not found consistently in the literature (Kanberg et al, 2023). Signs of neuroin ammation has not only been observed in the CNS but also in the peripheral nervous system (Agergaard, Yamin Ali Khan, et al, 2023;Hejbøl et al, 2022). On the other hand, longitudinal brain imaging studies have shown damages in cortical areas associated with the olfactory system before versus after acute COVID-19, suggesting a speci c impact on those regions (Douaud et al, 2022).…”

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confidence: 99%

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Headache or Disturbed Smell and Taste During Acute COVID-19 as Predictors of Long COVID at One Year

Agergaard

2024

Preprint

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Purpose: Long coronavirus disease (COVID) poses a significant health concern for a substantial proportion of COVID-19 patients. Viral pathogenesis studies suggest the potential of central nervous system (CNS) affection in the acute phase of COVID-19 predicting long COVID. This study investigates whether acute COVID-19 symptoms, particularly headache and disturbed smell and taste, predict manifestations of long COVID. Methods: This prospective cohort study included COVID-19 patients hospitalized between March 2020, and May 2021. One year after discharge, patients responded to a symptom questionnaire. Logistic regression analysis was used to determine the odds ratio (OR) for these outcomes. Results: Of 288 eligible patients, 111 responded to the follow-up questionnaire. At 1 year follow-up, disturbed smell and taste during acute COVID-19 did not elevate the risk of long COVID. However, patients with acute headache demonstrated a tendency towards an elevated risk of CNS-related long COVID. Notably, this risk significantly increased in patients reporting dizziness (adjusted OR=4.20; 95% confidence interval (CI) 1.19 - 14.85). Neither disturbed smell and taste nor headache during acute COVID-19 indicated a statistically significant risk of worsening in fatigue, health, or total symptom score at 1-year follow-up. Conclusion: Headache, and not disturbed smell and taste, predicted CNS-related long COVID. Further research is warranted to clarify pathways connecting CNS-related symptoms during acute COVID-19 with long COVID, aiding the efforts of addressing the range of symptoms observed among long COVID patients and developing effective interventions.

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confidence: 53%

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confidence: 99%

Headache or Disturbed Smell and Taste During Acute COVID-19 as Predictors of Long COVID at One Year

Agergaard

2024

Preprint

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“…Noto and co-workers found disabling muscle fatigability and high incidence of activity dependent block using stimulated sfEMG but there was no correlation between sfEMG results and clinical fatigue scores ( Noto et al, 2013 ). However, in a recent study, long COVID fatigue scores were correlated to higher values of jitter ( Agergaard et al, 2023 ) (see the long COVID section for details).…”

Section: Measuring Fatigue and Fatigabilitymentioning

confidence: 90%

“…More recently, mean jitter was found increased in up to 25 % of long Covid patients, using sfEMG. Importantly, these peripheral neuromuscular junction findings inversely correlated with quality-of-life scores ( Agergaard et al, 2023 ). Collectively, these studies suggest that skeletal muscle dysfunction and neuromuscular junction instability may play an important role in post-Covid fatigability and fatigue even without overt clinical myopathy.…”

Section: Fatigability In Me/cfs and Long Covidmentioning

confidence: 99%

The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability

Tankisi,

Versace,

Kuppuswamy

et al. 2024

Clinical Neurophysiology Practice

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“…The absence of peripheral nerve dysfunction in the nerve conduction assessments in conjunction with the presence of myopathic indices corroborates the predominantly myogenic nature of the EMG findings. This is consistent with other studies reporting changes of myogenic origin in patients with PCC, although a recent study pointed to structural muscle problems and exercise-induced myopathy . Collectively, these observations highlight muscular impairment in patients with PCC, which is further supported by the observed decrease in isometric muscle strength.…”

Section: Discussionmentioning

confidence: 99%

Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition

Tryfonos,

Pourhamidi,

Jörnåker

et al. 2024

JAMA Netw Open

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ImportanceMany patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration.ObjectiveTo assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC.Design, Setting, and ParticipantsIn this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited.InterventionsAfter comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise.Main Outcomes and MeasuresThe primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC.ResultsThirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: −6.8 mL/kg/min; 95% CI, −10.7 to −2.9 mL/kg/min; P &lt; .001) and less isometric knee extension muscle strength (mean difference: −37 Nm; 95% CI, −67 to −7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, −26.5 minutes/d; 95% CI, −42.0 to −11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing.Conclusions and RelevanceIn this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC.Trial RegistrationClinicalTrials.gov Identifier: NCT05445830

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Myopathy as a cause of Long COVID fatigue: Evidence from quantitative and single fiber EMG and muscle histopathology

Cited by 8 publications

References 30 publications

Headache or Disturbed Smell and Taste During Acute COVID-19 as Predictors of Long COVID at One Year

Headache or Disturbed Smell and Taste During Acute COVID-19 as Predictors of Long COVID at One Year

The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability

Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition

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