Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID: Postexertional Symptom Exacerbation is an Abnormal Response to Exercise/Activity

Prolonged symptoms after infection with the novel coronavirus 2019 (SARS-COV-2) are an emerging challenge to individual patients, society, and clinicians. In a previous post on the JOSPT Blog, we identified several lessons from research and clinical practice in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that are important lessons for long COVID. The purpose of this post is to discuss the phenomenon of postexertional symptom exacerbation (PESE) and its clinical identification to recognize the potential onset of long COVID.

Data from a large international web-based patient survey indicate substantial symptom overlap between postacute SARS-COV-2 infection (long COVID) and ME/CFS at 6 months following the onset of first symptoms. Three quarters of respondents noted disabling fatigue and over half noted cognitive dysfunction.4 A unique finding of this survey was that 75% of respondents noted PESE, which is a worsening of symptoms after activity/exercise.4 PESE is foundational to the diagnosis of ME/CFS and it is common with long COVID.4,5 This observation suggests we can further extend lessons from ME/CFS to develop our understanding of long COVID.

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Source: Todd E. Davenport Staci R. Stevens Jared Stevens Christopher R. Snell J. Mark Van Ness. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID: Postexertional Symptom Exacerbation is an Abnormal Response to Exercise/Activity. Published online on February 2, 2022 https://doi.org/10.2519/jospt.blog.20220202

Oral Minocycline Challenge as a Potential First-Line Therapy for Myalgic Encephalomyelitis and Long Covid-19 Syndrome

Abstract:

Chronic fatigue syndrome characterized by severe disabling fatigue, prolonged post-exertional malaise, and unrefreshing sleep markedly reduces the activities of daily living and impairs the quality of life.

Central nervous system dysfunction associated with myalgic encephalomyelitis (ME) has been postulated as the main cause of chronic fatigue syndrome.

Recently, oral minocycline therapy has been reported to exert favorable therapeutic effects in some patients with ME, especially in the initial stage of the disease, although many patients discontinued treatment in the first few days because of acute adverse effects such as nausea and/or dizziness.

Minocycline appeared to exert a variety of biologic actions against neural inflammation that are independent of their anti-microbial activity, including anti-inflammatory, immunomodulatory, and neuroprotective effects.

In recent years, it has been noted that COVID-19 disease may cause persistent signs and symptoms described as post-COVID syndrome or long COVID, in which the clinical presentation is remarkably similar to those seen in patients with ME.

A wide range of infectious agents have been suggested to trigger the development of ME, and one of such pathogens may be the COVID-19 virus.

Recently, I had a valuable experience of a 22-year-old female patient with a 14-month duration of long COVID who completely recovered from ME-like symptoms after treatment with minocycline. This case suggests that oral minocycline could be an effective first-line therapy for long COVID-19, although a large scale of trial is obviously needed to justify the therapy.

Source: Miwa K. Oral Minocycline Challenge as a Potential First-Line Therapy for Myalgic Encephalomyelitis and Long Covid-19 Syndrome. Ann Clin Med Case Rep. 2022; V8(7): 1-4 https://acmcasereport.com/wp-content/uploads/2022/01/ACMCR-v8-1710.pdf  (Full article available as PDF file)

Myalgic encephalomyelitis/chronic fatigue syndrome post coronavirus disease 2019

Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been the most impactful infectious disease in the 21st century. The SARS-CoV-2 pandemic significantly increased the number of patients and deaths worldwide. Long-course diseases related to COVID-19, which present with persistent reparatory distress or fatigue (so-called long COVID) have been reported in adult and pediatric patients since the latter half of 2020. Long-COVID is observed as a persistent symptom after the acute phase of the disease.1 Recent research suggested that it can present with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).2 We report a case of long COVID to contribute to the body of knowledge regarding this disease, which has not been well investigated in children.

A 14-year-old boy with well controlled asthma, controlled by a long-acting muscarinic antagonist, long-acting beta-agonist, and corticosteroid inhaler, was admitted to our hospital for severe fatigue and appetite loss. He suffered from COVID-19 diagnosed using reverse transcription polymerase chain reaction 90 days prior to hospitalization. He presented with a low-grade fever, mild cough, dysgeusia, and dysosmia. He was placed under quarantine in a hotel room for 6 days. His low-grade fever and mild cough resolved after 10 days, while the dysgeusia and dysosmia disappeared within a month. He presented with gradually progressive upper limb muscle weakness, severe fatigue, and difficulty concentrating (so-called “brain fog”) 20 days before hospitalization (70 days after the onset of COVID-19). He was unable to commute to attend junior high school. Three days before hospitalization, the patient did not eat due to appetite loss. He received oral prednisolone (20 mg/day) and Kanpō medicine (Rikkun-shito and Hotyu-ekkito). However, his symptoms were not relieved, and the patient was hospitalized. At the time of hospitalization, he did not present with fever, dyspnea, or desaturation. Physical examination revealed an upper limb strength of grade 4 on manual muscle testing, but the tendon reflexes or sensory/motor nerve abnormalities were not noted in the extremities. Blood tests revealed normal white blood cell and C-reactive protein levels. Epstein–Barr virus and human immunodeficiency virus antibodies and antinuclear antibodies were not detected. The 10 min standing test revealed an increase of 52 heartbeats after standing at an upright position (from 81 to 133 beats/min). The patient was diagnosed with postural orthostatic tachycardia syndrome (POTS). After the test, the patient complained of worsening fatigue, suggesting post-exertional malaise (PEM), a specific characteristic of ME/CFS. Based on the clinical course and physical examination, the patient was diagnosed with ME/CFS due to long-COVID. Oral prednisolone was discontinued, while the Kanpō medicine was continued. The patient then developed alopecia. Meanwhile, his muscle weakness and fatigue were alleviated by activity restriction due to hospitalization. On the 14th day of admission, he was discharged because his appetite improved, and he was referred to a hospital that specifically tended to chronic fatigue syndrome patients. Neither brain imaging nor electroencephalography were performed throughout the patient’s hospitalization.

The National Institute for Health Research in England classified long-COVID into four categories, namely, post-ICU syndrome, long-term organ damage, post-viral syndrome, and an entirely novel syndrome.3 Myalgic encephalomyelitis/chronic fatigue syndrome is typical of post-viral syndromes in adults, and similar cases have also been reported in children.4 Females are more likely to suffer from the disease, but males could also be affected. The exacerbation of symptoms upon exertion is known as PEM; avoiding extensive work is the essential aspect of ME/CFS management.5 In this case, the patient’s muscle fatigue and weakness dramatically improved with activity restriction due to hospitalization. This strategy may be useful for treating the severe exacerbation of ME/CFS. Chronic fatigue syndrome is diagnosed based on the persistence of symptoms for more than 6 months.2 This implies that patients have to wait for 6 months to be diagnosed with ME/CFS. Thus, new diagnostic criteria, specifically for ME/CFS due to COVID, are required to allow early intervention. Petracek et al. reported that POTS might be an early sign of COVID-induced ME/CFS,4 POTS is considered to be a viable diagnostic criterion. To prepare for a surge of pediatric ME/CFS, the diagnostic and treatment algorithm for the disease should be standardized, and physicians need to know about or recognize the disease.

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Source: Kusama Y, Fukui S, Maruyama M, Kamimura K, Maihara T. Myalgic encephalomyelitis/chronic fatigue syndrome post coronavirus disease 2019. Pediatr Int. 2022 Jan;64(1):e14976. doi: 10.1111/ped.14976. PMID: 35143110. https://onlinelibrary.wiley.com/doi/10.1111/ped.14976 (Full text)

Pediatric Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Overlaps and Opportunities

David Spodick once wrote: “We must view published material critically (if not biblically), for too often the ‘Conclusions’ giveth, but the ‘Materials and Methods’ taketh away.” In the December 2021 issue of the Pediatric Infectious Diseases Journal, Zimmermann et al provide a masterful application of Spodick’s exhortation. Their review of the existing evidence regarding long COVID in children enumerates important methodologic challenges in interpreting this literature, including the heterogeneity of available case definitions for long COVID, differences in the time intervals in which symptoms are ascertained, variability regarding which symptoms are included under the rubric of long COVID, and whether laboratory confirmation of the initial COVID infection is required. Additionally, the authors emphasize that without control groups in many of these studies, and in light of the overlap of some long COVID symptoms with symptoms of prolonged social isolation, it is difficult to discern which symptoms are attributable to the general pandemic circumstances rather than the COVID-19 infection itself. Despite such limitations, it is clear that pediatric patients are at risk for prolonged symptoms following acute SARS-CoV-2 infection. Although many persistent symptoms, such as anosmia, dysgeusia and shortness of breath are unique to the post-COVID state, many other symptoms such as fatigue, cognitive dysfunction, lightheadedness and postexertional malaise overlap with symptoms found in myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). In this commentary, we review case definitions for long COVID and ME/CFS, emphasize recent research findings on the biologic basis of ME/CFS, discuss the overlap with long COVID, and consider opportunities posed by the pandemic to improve the understanding of both conditions

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Source: Siberry VGR, Rowe PC. Pediatric Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Overlaps and Opportunities. Pediatr Infect Dis J. 2022 Feb 4. doi: 10.1097/INF.0000000000003477. Epub ahead of print. PMID: 35121715. https://journals.lww.com/pidj/Citation/9000/Pediatric_Long_COVID_and_Myalgic.95546.aspx (Full text)

Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long‐Haul COVID‐19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Background and Objectives: Symptoms and hemodynamic findings during orthostatic stress have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but little work has directly compared patients from these two groups. To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls.
Materials and Methods: We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress.
Results: There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response.
Conclusions: The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.
Source: Campen CMCv, Rowe PC, Visser FC. Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Medicina. 2022; 58(1):28. https://doi.org/10.3390/medicina58010028  (Full text)

Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)—A Systemic Review and Comparison of Clinical Presentation and Symptomatology

Abstract:

Background and Objectives: Long COVID defines a series of chronic symptoms that patients may experience after resolution of acute COVID-19. Early reports from studies with patients with long COVID suggests a constellation of symptoms with similarities to another chronic medical illness-myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A review study comparing and contrasting ME/CFS with reported symptoms of long COVID may yield mutualistic insight into the characterization and management of both conditions.

Materials and Methods: A systemic literature search was conducted in MEDLINE and PsycInfo through to 31 January 2021 for studies related to long COVID symptomatology. The literature search was conducted in accordance with PRISMA methodology.

Results: Twenty-one studies were included in the qualitative analysis. Long COVID symptoms reported by the included studies were compared to a list of ME/CFS symptoms compiled from multiple case definitions. Twenty-five out of 29 known ME/CFS symptoms were reported by at least one selected long COVID study.

Conclusions: Early studies into long COVID symptomatology suggest many overlaps with clinical presentation of ME/CFS. The need for monitoring and treatment for patients post-COVID is evident. Advancements and standardization of long COVID research methodologies would improve the quality of future research, and may allow further investigations into the similarities and differences between long COVID and ME/CFS.

Source: Wong TL, Weitzer DJ. Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)-A Systemic Review and Comparison of Clinical Presentation and Symptomatology. Medicina (Kaunas). 2021 Apr 26;57(5):418. doi: 10.3390/medicina57050418. PMID: 33925784; PMCID: PMC8145228. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145228/  (Full text)

Our Evolving Understanding of ME/CFS

Abstract:

The potential benefits of the scientific insights gleaned from years of treating ME/CFS for the emerging symptoms of COVID-19, and in particular Longhaul- or Longhauler-COVID-19 are discussed in this opinion article. Longhaul COVID-19 is the current name being given to the long-term sequelae (symptoms lasting beyond 6 weeks) of SARS-CoV-2 infection. Multiple case definitions for ME/CFS exist, but post-exertional malaise (PEM) is currently emerging as the ‘hallmark’ symptom. The inability to identify a unique trigger of ME/CFS, as well as the inability to identify a specific, diagnostic laboratory test, led many physicians to conclude that the illness was psychosomatic or non-existent. However, recent research in the US and the UK, championed by patient organizations and their use of the internet and social media, suggest underlying pathophysiologies, e.g., oxidative stress and mitochondrial dysfunction. The similarity and overlap of ME/CFS and Longhaul COVID-19 symptoms suggest to us similar pathological processes.

We put forward a unifying hypothesis that explains the precipitating events such as viral triggers and other documented exposures: For their overlap in symptoms, ME/CFS and Longhaul COVID-19 should be described as Post Active Phase of Infection Syndromes (PAPIS). We further propose that the underlying biochemical pathways and pathophysiological processes of similar symptoms are similar regardless of the initiating trigger. Exploration of the biochemical pathways and pathophysiological processes should yield effective therapies for these conditions and others that may exhibit these symptoms. ME/CFS patients have suffered far too long. Longhaul COVD-19 patients should not be subject to a similar fate. We caution that failure to meet the now combined challenges of ME/CFS and Longhaul COVID-19 will impose serious socioeconomic as well as clinical consequences for patients, the families of patients, and society as a whole.

Source: Friedman KJ, Murovska M, Pheby DFH, Zalewski P. Our Evolving Understanding of ME/CFS. Medicina (Kaunas). 2021 Feb 26;57(3):200. doi: 10.3390/medicina57030200. PMID: 33652622. https://www.mdpi.com/1648-9144/57/3/200 (Full text)