Polyphenols as possible alternative agents in chronic fatigue: a review

Abstract:

Chronic fatigue syndrome (CFS) is a pathological state of extreme tiredness that lasts more than six months and may possess an impact on the social, emotional, or occupational functioning of an individual. CFS is characterized by profound disabling fatigue associated with infectious, rheumatological, and neurological symptoms.

The current pharmacological treatment for CFS does not offer a complete cure for the disease, and none of the available treatments show promising results.

The exact mechanism of the pathogenesis of the disease is still unknown, with current suggestions indicating the overlapping roles of the immune system, central nervous system, and neuroendocrine system.

However, the pathological mechanism revolves around inflammatory and oxidative stress markers.

Polyphenols are the most abundant secondary metabolites of plant origin, with potent antioxidant and anti-inflammatory effects, and can exert protective activity against a whole range of disorders.

The current review is aimed at highlighting the emerging role of polyphenols in CFS from both preclinical and clinical studies. Numerous agents of this class have shown promising results in different in vitro and in vivo models of chronic fatigue/CFS, predominantly by counteracting oxidative stress and the inflammatory cascade.

The clinical data in this regard is still very limited and needs expanding through randomized, placebo-controlled studies to draw final conclusions on whether polyphenols may be a class of clinically effective nutraceuticals in patients with CFS.

Source: Ullah, H., Khan, A., Riccioni, C. et al. Polyphenols as possible alternative agents in chronic fatigue: a review. Phytochem Rev (2022). https://doi.org/10.1007/s11101-022-09838-9 (Full text)

Fatigue in Covid-19 survivors: The potential impact of a nutritional supplement on muscle strength and function

Summary:

Background: Fatigue with reduced tolerance to exercise is a common persistent long-lasting feature amongst COVID-19 survivors. The assessment of muscle function in this category of patients is often neglected.

Aim: To evaluate the potential impact of a daily supplementation based on amino acids, minerals, vitamins, and plant extracts (Apportal®) on muscle function, body composition, laboratory parameters and self-rated health in a small group of COVID-19 survivors affected by fatigue.

Methods: Thirty participants were enrolled among patients affected by physical fatigue during or after acute COVID-19 and admitted to the post-COVID-19 outpatient service at Fondazione Policlinico Gemelli in Rome between 1st March 2021 and 30th April 2021. All participants were evaluated at first visit (t0) and at control visit (t1), after taking a daily sachet of Apportal® for 28 days. Muscle function was analyzed using hand grip strength test, exhaustion strength time and the number of repetitions at one-minute chair stand test. Body composition was assessed with bioelectrical impedance analysis (BIA). Laboratory parameters, including standard blood biochemistry and ferritin levels, were evaluated at the first visit and during the control visit. A quick evaluation of self-rated health, before COVID-19, at t0 and t1, was obtained through a visual analogue scale (VAS).

Results: Participants aged 60 years and older were 13 (43%). Females represented the 70% of the study sample. Participants hospitalized for COVID-19 with low-flow oxygen supplementation represented the 43.3% of the study sample while 3.3% received noninvasive ventilation (NIV) or invasive ventilation. Hand grip strength improved from 26.3 Kg to 28.9 Kg (p < 0.05) at t1 as compared to t0. The mean time of strength exhaustion increased from 31.7 s (sec) at t0 to 47.5 s at t1 (p < 0.05). Participants performed a higher number of repetitions (28.3 vs. 22.0; p < 0.05) during the one-minute chair stand test at t1 as compared to t0. A trend, although not significant, in reduction of ferritin levels was found after nutritional supplementation (94.4 vs. 84.3, respectively; p = 0.01). The self-rated health status increased by at least 13 points (t0, mean 57.6 ± 5.86; t1, mean 71.4 ± 6.73; p < 0.05).

Conclusion: After 28 days of nutritional supplementation with Apportal® in COVID-19 survivors affected by fatigue with reduced tolerance to exercise, we found a significant improvement in means of muscle strength and physical performance, associated with enhancement of self-rated health status between t0 and t1.

Source: Vincenzo Galluzzo, Maria Beatrice Zazzara, Francesca Ciciarello, Giulia Savera, Cristina Pais, Riccardo Calvani, Anna Picca, Emanuele Marzetti, Francesco Landi, Matteo Tosato, Steering Committee, Francesco Landi, Elisa Gremese, Coordination, Roberto Bernabei, Massimo Fantoni, Antonio Gasbarrini, Field investigators, Gastroenterology team, Serena Porcari, Carlo Romano Settanni, Geriatric team, Francesca Benvenuto, Giulia Bramato, Vincenzo Brandi, Angelo Carfì, Francesca Ciciarello, Sofia Fabrizi, Vincenzo Galluzzo, Maria Rita Lo Monaco, Anna Maria Martone, Emanuele Marzetti, Carmen Napolitano, Francesco Cosimo Pagano, Cristina Pais, Sara Rocchi, Elisabetta Rota, Andrea Salerno, Matteo Tosato, Marcello Tritto, Maria Beatrice Zazzara, Riccardo Calvani, Lucio Catalano, Anna Picca, Giulia Savera, Francesco Paolo Damiano, Alessandra Rocconi, Alessandro Galliani, Giovanni Spaziani, Salvatore Tupputi, Camilla Cocchi, Flavia Pirone, Federica D’Ignazio, Stefano Cacciatore, Infectious disease team, Roberto Cauda, Enrica Tamburrini, A. Borghetti, Simona Di Gianbenedetto, Rita Murri, Antonella Cingolani, Giulio Ventura, E. Taddei, D. Moschese, A. Ciccullo, A. Dusina, Internal Medicine team, Leonardo Stella, Giovanni Addolorato, Francesco Franceschi, Gertrude Mingrone, M.A. Zocco, Microbiology team, Maurizio Sanguinetti, Paola Cattani, Simona Marchetti, Brunella Posteraro, M. Sali, Neurology team, Alessandra Bizzarro, Alessandra Lauria, Ophthalmology team, Stanislao Rizzo, Maria Cristina Savastano, G. Gambini, G.M. Cozzupoli, C. Culiersi, Otolaryngology team, Giulio Cesare Passali, Gaetano Paludetti, Jacopo Galli, F. Crudo, G. Di Cintio, Y. Longobardi, L. Tricarico, M. Santantonio, Pediatric team, Danilo Buonsenso, P. Valentini, D. Pata, D. Sinatti, C. De Rose, Pneumology team, Luca Richeldi, Francesco Lombardi, A. Calabrese, Paolo Maria Leone, Maria Rosaria Calvello, Enrica Intini, Giuliano Montemurro, Psychiatric team, Gabriele Sani, Delfina Janiri, Alessio Simonetti, G. Giuseppin, M. Molinaro, M. odica, Radiology team, Luigi Natale, Anna Rita Larici, Riccardo Marano, Rheumatology team, Annamaria Paglionico, Luca Petricca, Luca Gigante, G. Natalello, A.L. Fedele, M.M. Lizzio, B. Tolusso, Clara Di Mario, S. Alivernini, Vascular team, Angelo Santoliquido, Luca Santoro, Angela Di Giorgio, Antonio Nesci, V. Popolla, Fatigue in Covid-19 survivors: The potential impact of a nutritional supplement on muscle strength and function, Clinical Nutrition ESPEN, 2022, ISSN 2405-4577, https://doi.org/10.1016/j.clnesp.2022.08.029. (Full text)

Coenzyme Q10 + alpha lipoic acid for chronic COVID syndrome

Abstract:

Chronic COVID syndrome is characterized by chronic fatigue, myalgia, depression and sleep disturbances, similar to chronic fatigue syndrome (CFS) and fibromyalgia syndrome. Implementations of mitochondrial nutrients (MNs) with diet are important for the clinical effects antioxidant. We examined if use of an association of coenzyme Q10 and alpha lipoic acid (Requpero®) could reduce chronic covid symptoms.

The Requpero study is a prospective observational study in which 174 patients, who had developed chronic-covid syndrome, were divided in two groups: The first one (116 patients) received coenzyme Q10 + alpha lipoic acid, and the second one (58 patients) did not receive any treatment. Primary outcome was reduction in Fatigue Severity Scale (FSS) in treatment group compared with control group. complete FSS response was reached most frequently in treatment group than in control group. A FSS complete response was reached in 62 (53.5%) patients in treatment group and in two (3.5%) patients in control group. A reduction in FSS core < 20% from baseline at T1 (non-response) was observed in 11 patients in the treatment group (9.5%) and in 15 patients in the control group (25.9%) (p < 0.0001).

To date, this is the first study that tests the efficacy of coenzyme Q10 and alpha lipoic acid in chronic Covid syndrome. Primary and secondary outcomes were met. These results have to be confirmed through a double blind placebo controlled trial of longer duration.

Source: Barletta MA, Marino G, Spagnolo B, Bianchi FP, Falappone PCF, Spagnolo L, Gatti P. Coenzyme Q10 + alpha lipoic acid for chronic COVID syndrome. Clin Exp Med. 2022 Aug 22. doi: 10.1007/s10238-022-00871-8. Epub ahead of print. PMID: 35994177.  https://link.springer.com/article/10.1007/s10238-022-00871-8 (Full text)

The Use of Palmitoylethanolamide in the Treatment of Long COVID: A Real-Life Retrospective Cohort Study

COVID-19 can cause symptoms that last weeks or months after the infection has gone, with a significant impairment of quality of life. Palmitoylethanolamide (PEA) is a naturally occurring lipid mediator that has an entourage effect on the endocannabinoid system mitigating the cytokine storm. The aim of this retrospective study is to evaluate the potential efficacy of PEA in the treatment of long COVID.
Patients attending the Neurological Out Clinic of the IRCCS Centro Neurolesi Bonino-Pulejo (Messina, Italy) from August 2020 to September 2021 were screened for potential inclusion in the study. We included only long COVID patients who were treated with PEA 600 mg two times daily for about 3 months. All patients performed the post-COVID-19 Functional Status (PCFS) scale. Thirty-three patients (10 males, 43.5%, mean age 47.8 ± 12.4) were enrolled in the study. Patients were divided into two groups based on hospitalization or home care observation. A substantial difference in the PCFS score between the two groups at baseline and after treatment with PEA were found. We found that smoking was a risk factor with an odds ratio of 8.13 CI 95% [0.233, 1.167]. Our findings encourage the use of PEA as a potentially effective therapy in patients with long COVID.
Source: Raciti L, De Luca R, Raciti G, Arcadi FA, Calabrò RS. The Use of Palmitoylethanolamide in the Treatment of Long COVID: A Real-Life Retrospective Cohort Study. Medical Sciences. 2022; 10(3):37. https://doi.org/10.3390/medsci10030037  https://www.mdpi.com/2076-3271/10/3/37/htm (Full text)

Dietary supplements, daily nutrient intake, and health-related quality of life among people with myalgic encephalomyelitis/chronic fatigue syndrome

There remains ambiguity surrounding the role of dietary supplementation and nutrient intake on the health status of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients, yet supplement use and dietary modification appear to be common among people with the condition. This pilot cross-sectional study aimed to investigate if supplement use or nutrient intake was associated with self-reported health-related quality of life (HRQoL) scores among Australians with ME/CFS.

The eligibility criteria for this study included being a resident of Australia, being aged between 18 and 65 years, and having received a formal diagnosis of ME/CFS from a physician. Participants completed a series of self-administered questionnaires querying sociodemographic information, symptom presentation, HRQoL, routine supplement use, and nutrient intake. The 36-item Short-Form Health Survey version 2 (SF-36) was employed to assess participants’ HRQoL. Daily nutrient intake was estimated from participants’ responses to the Dietary Questionnaire for Epidemiological Studies (Cancer Council Victoria, Australia). Multiple linear regression analysis was performed for each of the eight SF-36 domains. Age, gender, body mass index, employment, education were controlled variables in each model, with supplement and nutrient variables entered in a stepwise manner.

Twenty-four Australians with ME/CFS, 54.2% of which met the International Consensus Criteria case definition for ME/CFS, participated in the study. Three of the eight regression models were statistically significant, being the ‘role limitations due to physical health problems’ (adjusted R 2 = 0.733, P < 0.001), ‘bodily pain’ (adjusted R 2 = 0.544, P = 0.004), and ‘general health perceptions’ (adjusted R 2 = 0.743, P < 0.001) SF-36 domains. Positive associations were observed between HRQoL and the routine use of vitamin C (ß = 0.300, P = 0.042) and herbal supplements (ß = 0.618, P < 0.001), as well as daily saturated fat (ß = 0.860, P < 0.001), total folate (ß = 0.710, P < 0.001), and calcium intake (ß = 0.897, P = 0.003). However, the routine use of evening primrose oil supplements (ß = -0.385, P = 0.006) and daily intakes of alpha-linolenic acid (ß = −0.543, P = 0.001), long chain omega-3 fatty acids (ß = −0.431, P = 0.017), and iodine (ß = −0.602, P = 0.034) were negatively associated with HRQoL scores. None of the supplements or nutrients studied had consistent associations with HRQoL across the three significant regression models.

The findings of this pilot study suggest that there may be links between dietary supplementation and nutrient intake with HRQoL among people with ME/CFS. Future studies should investigate supplement use, daily nutrient intake, and their relationships with HRQoL and symptom presentation among people with ME/CFS longitudinally and compared with healthy controls to further elucidate the role of supplements and nutrient intake in the management of ME/CFS.

Read the full study HERE.

Source: Weigel, B., Eaton-Fitch, N., Passmore, R., Cabanas, H., Staines, D., & Marshall-Gradisnik, S. (2022). Dietary supplements, daily nutrient intake, and health-related quality of life among people with myalgic encephalomyelitis/chronic fatigue syndrome. Proceedings of the Nutrition Society, 81(OCE3), E80. doi:10.1017/S0029665122001057 https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/dietary-supplements-daily-nutrient-intake-and-healthrelated-quality-of-life-among-people-with-myalgic-encephalomyelitischronic-fatigue-syndrome/F837EC4FE783FFAEB44F66F7748C11F6 (Full text)

Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease with a substantial social and economic impact on individuals and their community. Despite its importance and deteriorating impact, progresses in diagnosis and treatment of ME/CFS is limited. This is due to the unclear pathophysiology of the disease and consequently lack of prognostic biomarkers.

To investigate pathophysiology of ME/CFS, several potential pathologic hallmarks have been investigated; however, these studies have failed to report a consistent result. These failures in introducing the underlying reason for ME/CFS have stimulated considering other possible contributing mechanisms such as tryptophan (TRP) metabolism and in particular kynurenine pathway (KP).

KP plays a central role in cellular energy production through the production of nicotinamide adenine dinucleotide (NADH). In addition, this pathway has been shown to mediate immune response and neuroinflammation through its metabolites. This review, we will discuss the pathology and management of ME/CFS and provide evidence pertaining KP abnormalities and symptoms that are classic characteristics of ME/CFS. Targeting the KP regulation may provide innovative approaches to the management of ME/CFS.

Source: Kavyani B, Lidbury BA, Schloeffel R, Fisher PR, Missailidis D, Annesley SJ, Dehhaghi M, Heng B, Guillemin GJ. Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle? Cell Mol Life Sci. 2022 Jul 11;79(8):412. doi: 10.1007/s00018-022-04380-5. PMID: 35821534. https://link.springer.com/article/10.1007/s00018-022-04380-5  (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)

Intracellular Nutritional Biomarker Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subjects and Healthy Controls

Abstract:

Objectives

A comparison of the nutritional biomarkers between ME/CFS subjects and healthy controls (HC) was undertaken on secondary data collected from an IRB approved cross-sectional study in ME/CFS patients.

Methods

ME/CFS participants were recruited per the 2018 revised Canadian Clinical Case Definition for ME/CFS along with age matched HCs. Self-reported information on demographics and supplement use was collected, and body mass index calculated. HEI was calculated from Willet FFQ and multiple day 24-hour recall data, and severity of fatigue measured by Multidimensional Fatigue Inventory (MFI). Lymphocyte transformation assay by SpectraCell Lab (Houston, TX) was employed for intracellular micronutrient status. A series of two-tailed Mann-Whitney U tests (ɑ = 0.05) were performed for the non-parametric data expressed as mean ± standard error of the mean. All statistical analyses were conducted in IBM SPSS Statistics version 25 (Armonk, NY).

Results

Out of the 21 participants (11 ME/CFS and 10 HC), 82% of ME/CFS and 50% of HC were female. Higher fatigue scores were observed in ME/CFS (16.64 ± 1.36) than HC (10.78 ± 2.14). ME/CFS had better HEI scores (63.36 ± 13.44) than the HC (38.55 ± 12.29). However, despite better diet quality and supplementation, ME/CFS group showed lower intracellular Vitamin B3 and manganese (Mn) (86.3 ± 2.42 and 53.6 ± 2.81 respectively) but higher calcium (Ca) (57.5 ± 3.55) as compared to HC (97.2 ± 2.31, 64.5 ± 1.87 and 46.5 ± 0.96 respectively).

Conclusions

The results align with the current literature on indications of mitochondrial dysfunction in ME/CFS. Reduced intracellular vit B3 provides suboptimal production of the NAD(P)(H)-cofactor family, thus affecting mitochondrial function and consequently energy production. The aberration in energy metabolism is compounded by other factors, such as reduced Mn but higher Ca intracellular levels seen in this study indicating disruptions in oxidative stress pathways, resulting in debilitating fatigue experienced by individuals with ME/CFS.

Source: Priya Krishnakumar, Camila Jaramillo, Shawn Kurian, Wendy Levy, Cara Milman, Nadine Mikati, Fatma Huffman, Maria Abreu, Amanpreet Cheema, Intracellular Nutritional Biomarker Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subjects and Healthy Controls, Current Developments in Nutrition, Volume 6, Issue Supplement_1, June 2022, Page 745, https://doi.org/10.1093/cdn/nzac062.014

Dietary Recommendations for Post-COVID-19 Syndrome

Abstract:

At the beginning of the coronavirus disease (COVID-19) pandemic, global efforts focused on containing the spread of the virus and avoiding contagion. Currently, it is evident that health professionals should deal with the overall health status of COVID-19 survivors. Indeed, novel findings have identified post-COVID-19 syndrome, which is characterized by malnutrition, loss of fat-free mass, and low-grade inflammation. In addition, the recovery might be complicated by persistent functional impairment (i.e., fatigue and muscle weakness, dysphagia, appetite loss, and taste/smell alterations) as well as psychological distress.

Therefore, the appropriate evaluation of nutritional status (assessment of dietary intake, anthropometrics, and body composition) is one of the pillars in the management of these patients. On the other hand, personalized dietary recommendations represent the best strategy to ensure recovery. Therefore, this review aimed to collect available evidence on the role of nutrients and their supplementation in post-COVID-19 syndrome to provide a practical guideline to nutritionists to tailor dietary interventions for patients recovering from COVID-19 infections.

Source: Barrea L, Grant WB, Frias-Toral E, Vetrani C, Verde L, de Alteriis G, Docimo A, Savastano S, Colao A, Muscogiuri G. Dietary Recommendations for Post-COVID-19 Syndrome. Nutrients. 2022 Mar 20;14(6):1305. doi: 10.3390/nu14061305. PMID: 35334962; PMCID: PMC8954128. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954128/(Full text)

The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19)

Abstract:

SARS-CoV-2 virus, infecting human cells via its spike protein, causes Coronavirus disease 2019 (COVID-19). COVID-19 is characterized by shortness of breath, fever, and pneumonia and is sometimes fatal. Unfortunately, to date, there is still no definite therapy to treat COVID-19. Therefore, the World Health Organization (WHO) approved only supportive care. During the COVID-19 pandemic, the need to maintain a correct intake of nutrients to support very weakened patients in overcoming disease arose. The literature available on nutrient intake for COVID-19 is mainly focused on prevention. However, the safe intake of micro- and/or macro-nutrients can be useful either for preventing infection and supporting the immune response during COVID-19, as well as in the post-acute phase, i.e., “long COVID”, that is sometimes characterized by the onset of various long lasting and disabling symptoms. The aim of this review is to focus on the role of nutrient intake during all the different phases of the disease, including prevention, the acute phase, and finally long COVID.

Source: Motti ML, Tafuri D, Donini L, Masucci MT, De Falco V, Mazzeo F. The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19). Nutrients. 2022 Feb 26;14(5):1000. doi: 10.3390/nu14051000. PMID: 35267974; PMCID: PMC8912782. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912782/ (Full text)