Disorders of gut-brain interaction in post-acute COVID-19 syndrome

Abstract:

The novel coronavirus SARS-CoV-2 is responsible for the devastating pandemic which has caused more than 5 million deaths across the world until today. Apart from causing acute respiratory illness and multiorgan dysfunction, there can be long-term multiorgan sequalae after recovery, which is termed ‘long COVID-19’ or ‘post-acute COVID-19 syndrome’. Little is known about long-term gastrointestinal (GI) consequences, occurrence of post-infection functional gastrointestinal disorders and impact the virus may have on overall intestinal health.

In this review, we put forth the various mechanisms which may lead to this entity and possible ways to diagnose and manage this disorder. Hence, making physicians aware of this spectrum of disease is of utmost importance in the present pandemic and this review will help clinicians understand and suspect the occurrence of functional GI disease post recovery from COVID-19 and manage it accordingly, avoiding unnecessary misconceptions and delay in treatment.

Source: Golla R, Vuyyuru SK, Kante B, Kedia S, Ahuja V. Disorders of gut-brain interaction in post-acute COVID-19 syndrome. Postgrad Med J. 2022 Jul 1:postgradmedj-2022-141749. doi: 10.1136/pmj-2022-141749. Epub ahead of print. PMID: 35777934. https://pmj.bmj.com/content/early/2022/07/01/pmj-2022-141749 (Full text)

Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Some patients with acute COVID-19 are left with persistent, debilitating fatigue, cognitive impairment (“brain fog”), orthostatic intolerance (OI) and other symptoms (“Long COVID”). Many of the symptoms are like those of other post-infectious fatigue syndromes and may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common diagnostic laboratory tests are often unrevealing.

Methods: We evaluated whether a simple, standardized, office-based test of OI, the 10-min NASA Lean Test (NLT), would aggravate symptoms and produce objective hemodynamic and cognitive abnormalities, the latter being evaluated by a simple smart phone-based app.

Participants: People with Long COVID (N = 42), ME/CFS (N = 26) and healthy control subjects (N = 20) were studied just before, during, immediately after, 2 and 7 days following completion of the NLT.

Results: The NLT provoked a worsening of symptoms in the two patient groups but not in healthy control subjects, and the severity of all symptoms was similar and significantly worse in the two patient groups than in the control subjects (p < 0.001). In the two patient groups, particularly those with Long COVID, the NLT provoked a marked and progressive narrowing in the pulse pressure. All three cognitive measures of reaction time worsened in the two patient groups immediately following the NLT, compared to the healthy control subjects, particularly in the Procedural Reaction Time (p < 0.01).

Conclusions: A test of orthostatic stress easily performed in an office setting reveals different symptomatic, hemodynamic and cognitive abnormalities in people with Long COVID and ME/CFS, compared to healthy control subjects. Thus, an orthostatic challenge easily performed in an office setting, and the use of a smart phone app to assess cognition, can provide objective confirmation of the orthostatic intolerance and brain fog reported by patients with Long COVID and ME/CFS.

Source: Vernon SD, Funk S, Bateman L, Stoddard GJ, Hammer S, Sullivan K, Bell J, Abbaszadeh S, Lipkin WI, Komaroff AL. Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (Lausanne). 2022 Jun 23;9:917019. doi: 10.3389/fmed.2022.917019. PMID: 35847821; PMCID: PMC9285104. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9285104/ (Full text)

Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID

Background and Objectives: COVID-19 can be serious not only in the acute phase but also after the acute phase and some patients develop ME/CFS. There have been few studies on patients with long COVID in whom ME/CFS was diagnosed by physicians based on standardized criteria after examinations and exclusion diagnosis and not based on only subjective symptoms. The purpose of this study was to elucidate the detailed characteristics of ME/CFS in patients with long COVID.
Materials and Methods: A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period was from February 2021 to April 2022.
Results: Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females). The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS. The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies. Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS.
Conclusions: The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study.
Source: Tokumasu K, Honda H, Sunada N, Sakurada Y, Matsuda Y, Yamamoto K, Nakano Y, Hasegawa T, Yamamoto Y, Otsuka Y, Hagiya H, Kataoka H, Ueda K, Otsuka F. Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID. Medicina. 2022; 58(7):850. https://doi.org/10.3390/medicina58070850 https://www.mdpi.com/1648-9144/58/7/850/htm (Full text)

Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study

Abstract:

Despite the increasing prevalence of patients with Long Covid Syndrome (LCS), to date the pathophysiology of the disease is still unclear, and therefore diagnosis and therapy are a complex effort without any standardization. To address these issues, we performed a broad exploratory screening study applying state-of-the-art post-genomic profiling methods to blood plasma derived from three groups: 1) healthy individuals vaccinated against SARS-CoV-2 without exposure to the full virus, 2) asymptomatic fully recovered patients at least three months after SARS-CoV-2 infection, 3) symptomatic patients at least 3 months after a SARS-CoV-2 infection, here designated as Long Covid Syndrome (LCS) patients.

Multiplex cytokine profiling indicated slightly elevated cytokine levels in recovered individuals in contrast to LCS patients, who displayed lowest levels of cytokines. Label-free proteome profiling corroborated an anti-inflammatory status in LCS characterized by low acute phase protein levels and a uniform down-regulation of macrophage-derived secreted proteins, a pattern also characteristic for chronic fatigue syndrome (CFS).

Along those lines, eicosanoid and docosanoid analysis revealed high levels of omega-3 fatty acids and a prevalence of anti-inflammatory oxylipins in LCS patients compared to the other study groups. Targeted metabolic profiling indicated low amino acid and triglyceride levels and deregulated acylcarnithines, characteristic for CFS and indicating mitochondrial stress in LCS patients. The anti-inflammatory osmolytes taurine and hypaphorine were significantly up-regulated in LCS patients.

In summary, here we present evidence for a specific anti-inflammatory and highly characteristic metabolic signature in LCS which could serve for future diagnostic purposes and help to establish rational therapeutic interventions in these patients.

Source: Johannes J Kovarik, Andrea Bileck, Gerhard Hagn, Samuel M Meier Menches, Tobias Frey, Anna Kaempf, Marlene Hollenstein, Tarik Shoumariyeh, Lukas Skos, Birgit Reiter, Marlene C Gerner, Andreas Spannbauer, Ena Hasimbegovic, Doreen Schmidl, Gerhard Garhoefer, Mariann Gyoengyoesi, Klaus G Schmetterer, Christopher Gerner. Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study. medRxiv 2022.07.11.22277499; doi: https://doi.org/10.1101/2022.07.11.22277499 (Full study available as PDF file)

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

Abstract:

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation.

The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT-angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.

Source: Szewczykowski C, Mardin C, Lucio M, Wallukat G, Hoffmanns J, Schröder T, Raith F, Rogge L, Heltmann F, Moritz M, Beitlich L, Schottenhamml J, Herrmann M, Harrer T, Ganslmayer M, Kruse FE, Kräter M, Guck J, Lämmer R, Zenkel M, Gießl A, Hohberger B. Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation. Int J Mol Sci. 2022 Jun 29;23(13):7209. doi: 10.3390/ijms23137209. PMID: 35806214. https://www.mdpi.com/1422-0067/23/13/7209/htm (Full text)

Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study

Abstract:

Background: Up to 37.7% of patients experience symptoms beyond 12 weeks after infection with SARS-CoV-2. To date care for people with long covid has centred around multidisciplinary rehabilitation, self care and self pacing. No pharmacotherapy has been shown to be beneficial.

Methods: In this single centre interventional pre post study, the safety of Low Dose Naltrexone (LDN) was explored in patients with Post COVID-19 Syndrome (PCS), defined by NICE as patients with ongoing symptoms 12 or more weeks after initial infections with SARS-CoV-2 where alternative explanation for symptoms cannot be found. Patients were recruited through a Post COVID clinic, had a baseline quality of life questionnaire in symmetrical Likert format, were prescribed 2 months (1 mg month one, 2 mg month two) of LDN and repeated the same questionnaire at the end of the second month. Patients were monitored to adverse events.

Findings: In total 52 patients participated of whom 40(76.9%) were female. The median age was 43.5 years(IQR 33.2–49). Healthcare workers represented the largest occupational cohort n = 16(34.8%). The median time from diagnosis of COVID-19 until enrolment was 333 days (IQR 171–396.5). Thirty-eight participants (73.1%) were known to commence LDN, two of whom (5.3%) stopped taking LDN post commencement due to new onset diarrhoea and also described fatigue. In total 36(69.2%) participants completed the questionnaire at the end of the two-month period. Improvement was seen in 6 of 7 parameters measured; recovery from COVID-19, limitation in activities of daily living, energy levels, pain levels, levels of concentration and sleep disturbance (p ≤ 0.001), improvement in mood approached but was not significant (p = 0.054).

Conclusions: LDN is safe in patients with PCS and may improve well-being and reduce symptomatology in this cohort. Randomised control trials are needed to further explore this.

Source: Brendan O’Kelly, Louise Vidal, Tina McHugh, James Woo, Gordana Avramovic, John S. Lambert. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study. Brain, Behavior, & Immunity – Health; Volume 24, October 2022, 100485 https://www.sciencedirect.com/science/article/pii/S2666354622000758  (Full text)

Rapid improvement in severe long COVID following perispinal etanercept

Abstract:

Background: This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain. Optimal synaptic and brain network function require physiological levels of TNF. Neuroinflammation, including brain microglial activation and excess central TNF, can be a consequence of stroke or peripheral infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.

Methods: Standardized, validated measures, including the Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 meter Self-Paced Walk Test, 5 Times Sit-to-Stand Test and Grip Strength measured with a Jamar Dynamometer were used to quantitate changes in cognition, depression, fatigue and neurological function after a single 25mg perispinal etanercept dose in a patient with severe long COVID of 12 months duration.

Results: Following perispinal etanercept administration there was immediate neurological improvement. At 24 hours there were remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measureable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination and grip strength. Cognition, depression and fatigue were examined at 29 days; each remained substantially improved.

Conclusion: Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary. The robust results of the present case suggest that perispinal etanercept clinical trials studying long COVID populations with severe fatigue, depression and cognitive dysfunction may have improved ability to detect a treatment effect. Positron emission tomographic methods that image brain microglial activation and measurements of cerebrospinal fluid proinflammatory cytokines may be useful for patient selection and correlation with treatment effects, as well as provide insight into the underlying pathophysiology.

Source: Tobinick E, Spengler RN, Ignatowski TA, Wassel M, Laborde S. Rapid improvement in severe long COVID following perispinal etanercept. Curr Med Res Opin. 2022 Jul 6:1-23. doi: 10.1080/03007995.2022.2096351. Epub ahead of print. PMID: 35791687.  https://pubmed.ncbi.nlm.nih.gov/35791687/

Pale rider: the Spanish flu of 1918 and how it changed the world

Book Review:

Pale rider: The Spanish Flu of 1918 and How it Changed the World by Laura Spinney, Public Affairs; 1st edition (September 12, 2017)

Formerly Professor of Psychiatry, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

The COVID-19 pandemic has changed life for humanity, nothing is “normal” anymore! In the last 100 years, there has not been any similar event. The common feeling among professionals, planners, press, politicians, and people is that “life will not be the same as we knew it, after the pandemic.” Understanding the likely impact of the pandemic and its consequences would be valuable to humanity in general and mental health professionals in particular. Against this current world-shaking event, it is natural to look for similar events in human history. In this, the 1918 flu is the closest event to understand a variety of aspects of the current pandemic. The book, Pale Rider: The Spanish Flu of 1918 and how it changed the world, is one of the best books in this field.[1] That many people are looking at the 1918 flu can be seen by the number of articles in the lay press that have focused on the 1918 flu.[2],[3],[4],[5],[6],[7] Even now, a new book was published as latest as July 23, 2020.[8],[9]

Nevertheless, the book, under review, has 21 chapters with attractive chapter titles such as Like a Thief in the Night; The Doctor’s Dilemma; The Wrath of God; Chalking Doors with Crosses; Good Samaritans; The Human Factor; The Green Shoots of Recovery; Alternate Histories; and Health Care for all and Melancholy Muse.

Between the first case recorded on March 4, 1918, and the last case sometime in March 1920, it killed 50–100 million people, or between 2.5% and 5% of the global population. In terms of a single event causing major loss of life, it surpassed the First World War (17 million dead) and the Second World War (60 million dead). India was specially affected and lost around 6% of its population, the greatest loss in absolute numbers of any country in the world (an estimate of 13–18 million). The book has a special focus on India,[1] presented through the lives of Mahatma Gandhi, Tagore, Munshi Premchand, and Nirala and its impact on the Independence struggle.

Mahatma Gandhi was affected by the gastric variety of flu. At Gandhi’s ashram, several prominent members of the Independence Movement were laid low with flu. Gandhi was too feverish to speak or read; he couldn’t shake a sense of doom: “All interest in living had ceased.” Interestingly, Gandhi’s reaction was: This protracted and first long illness in my life thus afforded me a unique opportunity to examine my principles and to test them. Rabindranath Tagore returned his knighthood as a reaction to the Jallianwala Bagh massacre, and observed that British were guilty of “the same kind of ignorance of the eternal laws which primitive people show when they hunt for some so-called witch to whom they ascribe the cause of their illness, while carrying the disease germs in their own blood.” Spinney observes that disease was a major preoccupation in the writing that emerged in the 1920s, where it dovetailed with ideas about the need to reform the caste system and throw off the yoke of British rule. Munshi Premchand became the self-styled “chronicler of village life” around 1918 when he was living in the United Provinces (Uttar Pradesh), where the Spanish flu claimed an estimated 2–3 million lives alone. Also living there at that time was the poet Nirala, who lost his wife and many other members of his family to the flu. He later recalled seeing the River Ganges “swollen with dead bodies.” This was the strangest time in my life. My family disappeared in the blink of an eye.

There are sections in the book describing the feelings of anxiety accompanying the acute phase of the disease, and reports of people killing themselves while delirious. Following recovery, some patients found themselves plunged into a lingering state of lassitude and despair. Norwegian epidemiologist Svenn-Erik Mamelund studied asylum records in his country from 1872 to 1929 and found that, every year, in which there was no pandemic of influenza, only a few cases were admitted of mental illness associated with flu. However, in each of the 6 years following the 1918 pandemic, the average number of such admissions was seven times higher than in those nonpandemic years (emphasis added). Mamelund speculates that the patients admitted in those 6 years were survivors of Spanish flu who were suffering from what today we would call “postviral or chronic fatigue syndrome.”

The book provides similar creative responses in a number of countries following the pandemic. The paragraph about controversies about the quarantine makes for contemporary reading: “Quarantine and other disease containment strategies place the interests of the collective over those of the individual. When the collective is very large, those strategies have to be imposed in a top-down fashion. But mandating a central authority to act in the interests of the collective potentially creates two kinds of problems. First, the collective may have competing priorities-the need to make money, or the need to raise an army-and deny or water-down the authority’s powers of enforcement. Second, the rights of individuals risk getting trampled on, especially if the authority abuses the measures placed at its disposal.”

One of the quotes from the book can portend what we can expect in the coming years in the country. Spinney notes, “The 1918 pandemic accelerated the pace of change in the first half of the twentieth century, and helped shape our modern world. It influenced the course of the First World War and arguably, contributed to the Second. It pushed India closer to Independence, South Africa closer to Apartheid, and Switzerland to the brink of Civil War. It ushered in universal healthcare and alternative medicine, our love of fresh air and our passion for sport, and it was probably responsible, at least in part, for the obsession of twentieth-century artists with all the myriad ways in which the human body can fail.”

The book made me realize that the current pandemic will bring about extensive changes. Against this expected “mental health tsunami,” there are three tasks for each one of us: firstly, to document the experiences of individuals, families, communities, and the government; secondly, to identify the social factors contributing to vulnerabilities and resilience, to guide corrective actions; and lastly, to utilize the opportunity of heightened awareness of societal-level issues, to work toward addressing the predisposing causes for higher mortality and morbidity such as inequalities, intolerances, inadequate health infrastructure, the weak welfare network to support the vulnerable, and decentralization of powers and plans to enhance community participation.

I recommend it as an essential reading during the current pandemic period.

Source: Murthy R S. Pale rider: the spanish flu of 1918 and how it changed the world. Indian J Soc Psychiatry [serial online] 2020 [cited 2022 Jul 4];36, Suppl S1:189-90. Available from: https://www.indjsp.org/text.asp?2020/36/5/189/297158

Functional decline, long term symptoms and course of frailty at 3-months follow-up in COVID-19 older survivors, a prospective observational cohort study

Abstract:

Background: Aging is one of the most important prognostic factors increasing the risk of clinical severity and mortality of COVID-19 infection. However, among patients over 75 years, little is known about post-acute functional decline.

Objective: The aim of this study was to identify factors associated with functional decline 3 months after COVID-19 onset, to identify long term COVID-19 symptoms and transitions between frailty statesafter COVID-19 onset in older hospitalized patients.

Methods: This prospective observational study included COVID-19 patients consecutively hospitalized from March to December 2020 in Acute Geriatric Ward in Nantes University Hospital. Functional decline, frailty status and long term symptoms were assessed at 3 month follow up. Functional status was assessed using the Activities of Daily Living simplified scale (ADL). Frailty status was evaluated using Clinical Frailty Scale (CFS). We performed multivariable analyses to identify factors associated with functional decline.

Results: Among the 318 patients hospitalized for COVID-19 infection, 198 were alive 3 months after discharge. At 3 months, functional decline occurred in 69 (36%) patients. In multivariable analysis, a significant association was found between functional decline and stroke (OR = 4,57, p = 0,003), history of depressive disorder (OR = 3,05, p = 0,016), complications (OR = 2,24, p = 0,039), length of stay (OR = 1,05, p = 0,025) and age (OR = 1,08, p = 0,028). At 3 months, 75 patients described long-term symptoms (49.0%). Of those with frailty (CFS scores ≥5) at 3-months follow-up, 30% were not frail at baseline. Increasing frailty defined by a worse CFS state between baseline and 3 months occurred in 41 patients (26.8%).

Conclusions: This study provides evidence that both the severity of the COVID-19 infection and preexisting medical conditions correlates with a functional decline at distance of the infection. This encourages practitioners to establish discharge personalized care plan based on a multidimensional geriatric assessment and in parallel on clinical severity evaluation.

Source: Prampart S, Le Gentil S, Bureau ML, Macchi C, Leroux C, Chapelet G, de Decker L, Rouaud A, Boureau AS. Functional decline, long term symptoms and course of frailty at 3-months follow-up in COVID-19 older survivors, a prospective observational cohort study. BMC Geriatr. 2022 Jun 30;22(1):542. doi: 10.1186/s12877-022-03197-y. PMID: 35768781. https://bmcgeriatr.biomedcentral.com/articles/10.1186/s12877-022-03197-y (Full text)

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

Abstract:

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 diminished 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.

Source: Cash, A., Kaufman, D.L. 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. J Transl Med 20, 295 (2022). https://doi.org/10.1186/s12967-022-03488-3  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03488-3 (Full text)