Possible Application of Melatonin in Long COVID.

Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, "long COVID". Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially memory loss or "brain fog"), chronic fatigue, myalgia, and muscular weakness resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are of importance. Melatonin may be particularly effective at reducing the signs and symptoms of SARS-CoV-2 infection due to its functions as an antioxidant, anti-inflammatory, and immuno-modulatory agent. Melatonin is also a chronobiotic medication effective in treating delirium and restoring the circadian imbalance seen in COVID patients in the intensive care unit. Additionally, as a cytoprotector, melatonin aids in the prevention of several COVID-19 comorbidities, including diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases. This narrative review discusses the application of melatonin as a neuroprotective agent to control cognitive deterioration ("brain fog") and pain in the ME/CFS syndrome-like documented in long COVID. Further studies on the therapeutic use of melatonin in the neurological sequelae of SARS-CoV-2 infection are warranted.

Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial.

BACKGROUND: There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue. METHODS: ME/CFS and Long-COVID patients were enrolled in an open label dose escalating "Proof of Concept" non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection. RESULTS: 76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the "Chalder Fatigue Questionnaire" of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients' fatigue was significantly reduced by up to 46.8% in 6-weeks. CONCLUSIONS: Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted. Trial Registration https://clinicaltrials.gov/ct2/show/NCT04592354 Registered October 19, 2020. 1,000 mg BID Normalized Fatigue Data for Baseline, 2-weeks and 6-weeks evaluated by 3 Validated Fatigue Scoring Questionnaires.

Treatments of chronic fatigue syndrome and its debilitating comorbidities: a 12-year population-based study.

BACKGROUND: This study aims to provide 12-year nationwide epidemiology data to investigate the epidemiology and comorbidities of and therapeutic options for chronic fatigue syndrome (CFS) by analyzing the National Health Insurance Research Database. METHODS: 6306 patients identified as having CFS during the 2000-2012 period and 6306 controls (with similar distributions of age and sex) were analyzed. RESULT: The patients with CFS were predominantly female and aged 35-64 years in Taiwan and presented a higher proportion of depression, anxiety disorder, insomnia, Crohn's disease, ulcerative colitis, renal disease, type 2 diabetes, gout, dyslipidemia, rheumatoid arthritis, Sjogren syndrome, and herpes zoster. The use of selective serotonin receptor inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), Serotonin antagonist and reuptake inhibitors (SARIs), Tricyclic antidepressants (TCAs), benzodiazepine (BZD), Norepinephrine-dopamine reuptake inhibitors (NDRIs), muscle relaxants, analgesic drugs, psychotherapies, and exercise therapies was prescribed significantly more frequently in the CFS cohort than in the control group. CONCLUSION: This large national study shared the mainstream therapies of CFS in Taiwan, we noticed these treatments reported effective to relieve symptoms in previous studies. Furthermore, our findings indicate that clinicians should have a heightened awareness of the comorbidities of CFS, especially in psychiatric problems.

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease characterized by severe and disabling fatigue that fails to improve with rest; it is commonly accompanied by multifocal pain, as well as sleep disruption, and cognitive dysfunction. Even mild exertion can exacerbate symptoms. The prevalence of ME/CFS in the U.S. is estimated to be 0.5-1.5 % and is higher among females. Viral infection is an established trigger for the onset of ME/CFS symptoms, raising the possibility of an increase in ME/CFS prevalence resulting from the ongoing COVID-19 pandemic. Current treatments are largely palliative and limited to alleviating symptoms and addressing the psychological sequelae associated with long-term disability. While ME/CFS is characterized by broad heterogeneity, common features include immune dysregulation and mitochondrial dysfunction. However, the underlying mechanistic basis of the disease remains poorly understood. Herein, we review the current understanding, diagnosis and treatment of ME/CFS and summarize past clinical studies aimed at identifying effective therapies. We describe the current status of mechanistic studies, including the identification of multiple targets for potential pharmacological intervention, and ongoing efforts towards the discovery of new medicines for ME/CFS treatment.

Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19.

As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a persistent, debilitating, and unexplained fatigue disorder. We investigated psychological morbidities such as CFS and post-traumatic stress disorder (PTSD) among survivors of COVID-19 over 6 months. All COVID-19 survivors from the university-affiliated hospital of Tehran, Iran, were assessed 6 months after infection onset by a previously validated questionnaire based on the Fukuda guidelines for CFS/EM and DSM-5 Checklist for PTSD (The Post-traumatic Stress Disorder Checklist for DSM-5 or PCL-5) to determine the presence of stress disorder and chronic fatigue problems. A total of 120 patients were enrolled. The prevalence rate of fatigue symptoms was 17.5%. Twelve (10%) screened positive for chronic idiopathic fatigue (CIF), 6 (5%) for CFS-like with insufficient fatigue syndrome (CFSWIFS), and 3 (2.5%) for CFS. The mean total scores in PCL-5 were 9.27 ± 10.76 (range:0-44), and the prevalence rate of PTSD was 5.8%. There was no significant association after adjusting between CFS and PTSD, gender, comorbidities, and chloroquine phosphate administration. The obtained data revealed the prevalence of CFS among patients with COVID-19, which is almost similar to CFS prevalence in the general population. Moreover, PTSD in patients with COVID-19 is not associated with the increased risk of CFS. Our study suggested that medical institutions should pay attention to the psychological consequences of the COVID-19 outbreak.

Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

BACKGROUND: Rintatolimod is a selective TLR3 agonist, which has demonstrated clinical activity for ME/CFS in Phase II and Phase III double-blind, placebo-controlled, randomized, multi-site clinical trials. METHODS AND FINDINGS: A hypothesis-based post-hoc analysis of the Intent to Treat (ITT) population diagnosed with ME/CFS from 12 independent clinical sites of a Phase III trial was performed to evaluate the effect of rintatolimod therapy based on disease duration. The clinical activity of rintatolimod was evaluated by exercise treadmill tolerance (ETT) using a modified Bruce protocol. The ITT population (n = 208) was divided into two subsets of symptom duration. Patients with symptom duration of 2-8 years were identified as the Target Subset (n = 75); the remainder (<2 year plus >8 year) were identified as the Non-Target Subset (n = 133). Placebo-adjusted percentage improvements in exercise duration and the vertical rise for the Target Subset (n = 75) were more than twice that of the ITT population. The Non-Target Subset (n = 133) failed to show any clinically significant ETT response to rintatolimod when compared to placebo. Within the Target Subset, 51.2% of rintatolimod-treated patients improved their exercise duration by ≥25% (p = 0.003) despite reduced statistical power from division of the original ITT population into two subsets. CONCLUSION/SIGNIFICANCE: Analysis of ETT from a Phase III trial has identified within the ITT population, a subset of ME/CFS patients with ≥2 fold increased exercise response to rintatolimod. Substantial improvement in physical performance was seen for the majority (51.2%) of these severely debilitated patients who improved exercise duration by ≥25%. This magnitude of exercise improvement was associated with clinically significant enhancements in quality of life. The data indicate that ME/CFS patients have a relatively short disease duration window (<8 years) to expect a significant response to rintatolimod under the dosing conditions utilized in this Phase III clinical trial. These results may have direct relevance to the cognitive impairment and fatigue being experienced by patients clinically recovered from COVID-19 and free of detectable SARS-CoV-2. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00215800.