Longitudinal Progression of Patients with Long COVID Treated in a Post-COVID Clinic: A Cross-Sectional Survey

Abstract:

Background: In addition to the morbidity and mortality associated with acute infection, COVID-19 has been associated with persistent symptoms (>30 days), often referred to as Long COVID (LC). LC symptoms often cluster into phenotypes, resembling conditions such as fibromyalgia, postural orthostatic tachycardiac syndrome (POTS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). LC clinics have been established to best address the needs of LC patients and continuity of care. We developed a cross-sectional survey to assess treatment response through our LC Clinic (LCC).

Methods: A 25-question survey (1-10 Likert scale) was expert- and content-validated by LCC clinicians, patients, and patient advocates. The survey assessed LC symptoms and the helpfulness of different interventions, including medications and supplements. A total of 852 LCC patients were asked to complete the survey, with 536 (62.9%) responding.

Results: The mean time from associated COVID-19 infection to survey completion was 23.2 ± 6.4 months. The mean age of responders was 52.3 ± 14.1 (63% females). Self-reported symptoms were all significantly improved (P < .001) from the initial visit to the LCC (baseline) to the time of the follow-up survey. However, only 4.5% (24/536) of patients rated all symptoms low (1-2) at the time of the survey, indicating low levels of full recovery in our cohort. The patients rated numerous interventions as being helpful, including low-dose naltrexone (45/77; 58%), vagal nerve stimulation (18/34; 53%), and fisetin (28/44; 64%).

Conclusions: Patients report general improvements in symptoms following the initial LCC visit, but complete recovery rates remain low at 23.2 ± 6.4 months.

Source: Hurt RT, Yadav S, Schroeder DR, Croghan IT, Mueller MR, Grach SL, Aakre CA, Gilman EA, Stephenson CR, Overgaard J, Collins NM, Lawson DK, Thompson AM, Natividad LT, Mohamed Elfadil O, Ganesh R. Longitudinal Progression of Patients with Long COVID Treated in a Post-COVID Clinic: A Cross-Sectional Survey. J Prim Care Community Health. 2024 Jan-Dec;15:21501319241258671. doi: 10.1177/21501319241258671. PMID: 38813984. https://journals.sagepub.com/doi/10.1177/21501319241258671 (Full text)

An international survey of experiences and attitudes towards transcutaneous auricular vagus nerve stimulation for people with Myalgic Encephalomyelitis/chronic fatigue syndrome

Abstract:

Background and objectives: Myalgic encephalomyelitis (ME) is a complex, multi-system neurological condition. Dysfunction of the autonomic nervous system is a primary feature in diagnostic criteria, and management may include attempts to stimulate the parasympathetic nervous system. Transcutaneous auricular vagus nerve stimulation is an intervention that has been researched in neurological disorders, e.g. epilepsy, depression. While little evidence exists for its use in ME, this survey aims to explore the experiences and attitudes of people with ME to this intervention.

Methods: A 31-question online survey was devised and released on ME websites, Twitter and Facebook pages. People with ME read the information sheet and followed an online link to the survey. The survey was open for four weeks and all answers were anonymous.

Results: 116 responses were received. 56% of respondents reported favourable effects. Benefits of transcutaneous auricular vagus nerve stimulation were identified in relation to post exertional malaise, pain, gut problems, urinary problems, mental health, and the ability to leave the house. 67.2% of respondents would recommend the intervention to other people with ME. However, 4.3% would not recommend it and 6% reported it made them worse. 8.6% received support in setting up the device from healthcare workers.

Conclusion: The survey highlights that many people with ME experience significant benefits from using transcutaneous auricular vagus nerve stimulation; however due to potential negative effects there is the need for formal intervention studies to clearly identify safe parameters.

Source: Karen Leslie, Nicola Clague-Baker, Mohammad Abdelfattah Atallah Madi, Dawn Wiley, Andrea Parker, Michelle Bull & Natalie Hilliard. (2023) An international survey of experiences and attitudes towards transcutaneous auricular vagus nerve stimulation for people with Myalgic Encephalomyelitis/chronic fatigue syndrome, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2023.2286029 https://www.tandfonline.com/doi/abs/10.1080/21641846.2023.2286029

Complementary and alternative medicine for long COVID: a systematic review of randomized controlled trials

Abstract:

Background: Complementary and alternative medicine (CAM) interventions are growing in popularity as possible treatments for long COVID symptoms. However, comprehensive analysis of current evidence in this setting is still lacking.

Objective: This study aims to review existing published studies on the use of CAM interventions for patients experiencing long COVID through a systematic review.

Design: Systematic review of randomized controlled trials (RCTs).

Methods: A comprehensive electronic literature search was performed in multiple databases and clinical trial registries from September 2019 to January 2023. RCTs evaluating efficacy and safety of CAM for long COVID were included. Methodological quality of each included trial was appraised with the Cochrane ‘risk of bias’ tool. A qualitative analysis was conducted due to heterogeneity of included studies.

Results: A total of 14 RCTs with 1195 participants were included in this review. Study findings demonstrated that CAM interventions could benefit patients with long COVID, especially those suffering from neuropsychiatric disorders, olfactory dysfunction, cognitive impairment, fatigue, breathlessness, and mild-to-moderate lung fibrosis. The main interventions reported were self-administered transcutaneous auricular vagus nerve stimulation, neuro-meditation, dietary supplements, olfactory training, aromatherapy, inspiratory muscle training, concurrent training, and an online breathing and well-being program.

Conclusion: CAM interventions may be effective, safe, and acceptable to patients with symptoms of long COVID. However, the findings from this systematic review should be interpreted with caution due to various methodological limitations. More rigorous trials focused on CAM for long COVID are warranted in the future.

Source: Yang J, Lim KH, Lim KT, Woods JT, Mohabbat AB, Wahner-Roedler DL, Ganesh R, Bauer BA. Complementary and alternative medicine for long COVID: a systematic review of randomized controlled trials. Ther Adv Chronic Dis. 2023 Oct 11;14:20406223231204727. doi: 10.1177/20406223231204727. PMID: 37841213; PMCID: PMC10571674. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571674/ (Full text)

A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation

Abstract:

Long COVID, the postviral disorder caused by COVID-19, is expected to become one of the leading causes of disability in Europe. The cognitive consequences of long COVID have been described as “brain fog” and characterized by anxiety and depression, and by cognitive deficits. Long COVID is assumed to be a complex condition arising from multiple causes, including persistent brainstem dysfunction and disrupted vagal signaling.

We recommend the potential application of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON instrument to compensate for the cognitive decline and to ameliorate affective symptoms caused by long COVID. This technique enhances vagal signaling by directly activating the nuclei in the brainstem, which are hypoactive in long COVID to enhance mood and to promote attention, memory, and cognitive control-factors affected by long COVID.

Considering that atVNS is a non-pharmacological intervention, its ADD-ON to standard pharmaceutical agents will be useful for non-responders, making of this method a suitable tool. Given that atVNS can be employed as an ecological momentary intervention (EMI), we outline the translational advantages of atVNS in the context of accelerating the cognitive and affective recovery from long COVID.

Source: Colzato LS, Elmers J, Beste C, Hommel B. A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation. J Clin Med. 2023 Feb 2;12(3):1198. doi: 10.3390/jcm12031198. PMID: 36769845. https://www.mdpi.com/2077-0383/12/3/1198 (Full text)

Autonomic Nervous System Regulation Effects of Epipharyngeal Abrasive Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Associated With Chronic Epipharyngitis

Abstract:

Objective: To evaluate the autonomic nerve stimulation effect of epipharyngeal abrasive therapy (EAT) on myalgic encephalomyelitis/chronic fatigue syndrome (CFS) associated with chronic epipharyngitis. Heart rate variability analysis was performed. The study was conducted by analyzing heart rate variability.

Subjects and methods: A total of 29 patients with chronic epipharyngitis who underwent EAT from July 2017 to April 2018 were classified into two groups: 11 patients in the CFS group and 18 patients in the control group without CFS. The patients were classified as phase 1 during bed rest, phase 2 during nasal endoscopy, phase 3 during nasal abrasion, and phase 4 during oral abrasion. Electrocardiographic recordings were made, and autonomic function was compared and evaluated by measuring heart rate, coefficient of variation on R-R interval (CVRR), coefficient of component variance high frequency (ccvHF), and low frequency/ccvHF ratio (L/H) for each of the four phases. The Shapiro-Wilk test was performed to confirm the normality of the two groups, and the parametric test was selected. A repeated measures analysis of variance was performed to assess changes over time between the four events in the two groups. Multiple comparisons were corrected by the Bonferroni method. Comparisons between resting data and three events within each group were performed by paired t-test.

Results: The CFS group had an increased baseline heart rate compared to the control group, and the CFS group had a greater increase in parasympathetic activity and a decrease in heart rate with nasal abrasion. Oral abrasion elicited a pharyngeal reflex and increased heart rate and both sympathetic and parasympathetic activity.

Conclusion: The CFS group was in a state of dysautonomia due to autonomic overstimulation, with an elevated baseline heart rate. The CFS group was considered to be in a state of impaired autonomic homeostasis, with an increased likelihood that overstimulation would induce a pathological vagal reflex and the Reilly phenomenon would develop. The direct effects of EAT on the autonomic nervous system were considered to be vagus nerve stimulation and the regulation of autonomic function by opposing stimulation input to sympathetic and parasympathetic nerves. As an indirect effect, bleeding from the epipharyngeal mucosa due to abrasion was thought to restore the function of the cerebral venous and lymphatic excretory systems and the autonomic nerve center.

Source: Hirobumi I. Autonomic Nervous System Regulation Effects of Epipharyngeal Abrasive Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Associated With Chronic Epipharyngitis. Cureus. 2023 Jan 14;15(1):e33777. doi: 10.7759/cureus.33777. PMID: 36655156; PMCID: PMC9840732. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9840732/ (Full text)

Transcutaneous Vagus Nerve Stimulation in the Treatment of Long Covid-Chronic Fatigue Syndrome

Abstract:

Many patients do not recover following Covid infection. The resulting illness is called Long Covid. Because there is no agreed upon treatment for this ailment, we decided to do an open label pilot study using non-invasive, transcutaneous stimulation of the auricular branch of the vagus nerve. Inclusion criteria required the patient to fulfill criteria for having chronic fatigue syndrome. Fourteen patients provided evaluable data. Eight of these fulfilled our requirements for treatment success. Since our criterion for a successful study was that at least a third of patients had to show a positive response to treatment, this was a successful pilot that warrants a follow up study that is appropriately sham controlled.

Source: Benjamin H NatelsonMichelle BlateTiffany Soto. Transcutaneous Vagus Nerve Stimulation in the Treatment of Long Covid-Chronic Fatigue Syndrome.

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance

Abstract:

Myalgic encephalomyelitis, ME, previously also known as chronic fatigue syndrome (CFS) is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection.

The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation. Here we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting the vagus nuclei, and higher centers in the brain of ME-patients and induce a sustainable, ~30% reduction in overall symptom scores after eight weeks of treatment.

By performing longitudinal, systems-level monitoring of the blood immune system in these patients, we uncover chronic immune activation in ME, as well as immunological correlates of improvement that center around the IL-17 axis, gut-homing immune cells and reduced inflammation. The mechanisms of symptom relief remains to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We wish for these results to bring some hope to patients suffering from ME and inspire researchers to help test our new hypothesis that ME is a condition caused by a failure of inducing disease tolerance upon infection and persistent immune activation.

Source: Lucie ST Rodriguez, Christian Pou, Lakshmikanth Tadepally, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie-Qiang Li, Per Julin, Petter Brodin. Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance. bioRxiv
doi: https://doi.org/10.1101/2020.02.20.958249 https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1

Acupuncture and Moxibustion have Different Effects on Fatigue by Regulating the Autonomic Nervous System: A Pilot Controlled Clinical Trial

Abstract:

In order to investigate the different effects of acupuncture and moxibustion on chronic fatigue syndrome (CFS) and alterations in the autonomic nervous system by measuring heart rate variability (HRV).

Forty-five participants were recruited and randomly divided into 3 groups using a randomization schedule. The control group (CG, n = 15) and the acupuncture group (AG, n = 15) were treated by manipulation acupuncture, and the moxibustion group (MG, n = 15) was treated by indirect moxibustion. Primary outcomes were the scores of the Fatigue Assessment Instrument (FAI). Secondary outcomes were the HRV parameters which can reflect activity of the autonomic nervous system.

This trial considered both instantaneous changes and long-term effectiveness. FAI scores decreased after the 4th and 10th treatments in the 3 groups. The decrease in FAI in the MG was greater than that in the AG. Acupuncture was more effective in instantaneous changes of HRV and moxibustion in long-term aspects. Both acupuncture and moxibustion improved fatigue in CFS patients, but moxibustion was more effective.

The possible mechanism of the intervention may be through activation of the vagus nerve. Moxibustion was more effective than acupuncture in long-term treatment of CFS.

 

Source: Shu Q, Wang H, Litscher D, Wu S, Chen L, Gaischek I, Wang L, He W, Zhou H, Litscher G, Liang F. Acupuncture and Moxibustion have Different Effects on Fatigue by Regulating the Autonomic Nervous System: A Pilot Controlled Clinical Trial. Sci Rep. 2016 Nov 25;6:37846. doi: 10.1038/srep37846. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122953/ (Full article)