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COVID-19 and chronic fatigue syndrome: Is the worst yet to come?
Wostyn, P
Medical hypotheses. 2021;146:110469
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A proportion of COVID-19 patients develop post-COVID-19 syndrome, with long-term symptoms such as persistent fatigue, muscle pains, depressive symptoms, and non-restorative sleep, similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this article the author presents his medical hypothesis that, in a subset of patients at least, post-COVID-19 fatigue syndrome may result from damage to olfactory (smell) sensory neurons, which in turn may lead to toxic build-up within the central nervous system (CNS) through congestion of the glymphatic system (the waste clearance system of the CNS). Loss of smell and altered sensation of taste have been reported in 33–80% of COVID-19 patients but the underlying mechanisms are not yet known. Most of these patients regain their sense of smell within 1-3 weeks, suggesting that the virus does not affect the olfactory neurons but their surrounding supporting cells. Some patients, however, do not regain their sense of smell for months which may point to the destruction of neurons. A decrease in olfactory neurons may affect the flow of the cerebrospinal fluid (CSF) in an area important for CSF drainage. This may cause an increase in intracranial pressure (idiopathic intracranial hypertension, IIH) and congestion of the glymphatic system, which have been associated with chronic fatigue syndrome, as well as with headaches and tinnitus, symptoms also commonly seen in COVID-19 patients. The author states that if this hypothesis is confirmed, glymphatic-lymphatic drainage therapies, such as osteopathy, should be recommended as early treatment for patients with post-COVID-19 fatigue syndrome.
Abstract
There has been concern about possible long-term sequelae resembling myalgic encephalomyelitis/chronic fatigue syndrome in COVID-19 patients. Clarifying the mechanisms underlying such a "post-COVID-19 fatigue syndrome" is essential for the development of preventive and early treatment methods for this syndrome. In the present paper, by integrating insights pertaining to the glymphatic system and the nasal cerebrospinal fluid outflow pathway with findings in patients with chronic fatigue syndrome, idiopathic intracranial hypertension, and COVID-19, I provide a coherent conceptual framework for understanding the pathophysiology of post-COVID-19 fatigue syndrome. According to this hypothesis, this syndrome may result from damage to olfactory sensory neurons, causing reduced outflow of cerebrospinal fluid through the cribriform plate, and further leading to congestion of the glymphatic system with subsequent toxic build-up within the central nervous system. I further postulate that patients with post-COVID-19 fatigue syndrome may benefit from cerebrospinal fluid drainage by restoring glymphatic transport and waste removal from the brain. Obviously, further research is required to provide further evidence for the presence of this post-viral syndrome, and to provide additional insight regarding the relative contribution of the glymphatic-lymphatic system to it. Other mechanisms may also be involved. If confirmed, the glymphatic-lymphatic system could represent a target in combating post-COVID-19 fatigue syndrome. Moreover, further research in this area could also provide new insights into the understanding of chronic fatigue syndrome.
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Immediate and long-term consequences of COVID-19 infections for the development of neurological disease.
Heneka, MT, Golenbock, D, Latz, E, Morgan, D, Brown, R
Alzheimer's research & therapy. 2020;12(1):69
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Covid-19 may cause brain dysfunction evidenced by symptoms individuals experience once they have contracted the disease. Loss of smell, taste and confusion have all been reported by patients and a number of severe cases have reported incidences of stroke. These are all of concern, as Covid-19 can severely affect the elderly who ordinarily are the most likely to suffer from brain disorders. This small review paper of 27 studies stated that there are four possible ways in which Covid-19 may affect the brain, which put Covid-19 sufferers at an increased risk of long-term brain disorders. This was supported by findings, which showed one third of Covid-19 patients leave hospital with evidence of brain dysfunction. Inflammation was heavily reviewed by the authors as a possible causal factor. It was concluded that patients who survive Covid-19 infection are at an increased risk for developing brain disorders such as Alzheimer's disease, however it was acknowledged that further studies are required. Clinicians could use this study to understand the possible need for both short-term and long-term monitoring of brain function in individuals who have survived Covid-19, especially if they are elderly.
Abstract
Increasing evidence suggests that infection with Sars-CoV-2 causes neurological deficits in a substantial proportion of affected patients. While these symptoms arise acutely during the course of infection, less is known about the possible long-term consequences for the brain. Severely affected COVID-19 cases experience high levels of proinflammatory cytokines and acute respiratory dysfunction and often require assisted ventilation. All these factors have been suggested to cause cognitive decline. Pathogenetically, this may result from direct negative effects of the immune reaction, acceleration or aggravation of pre-existing cognitive deficits, or de novo induction of a neurodegenerative disease. This article summarizes the current understanding of neurological symptoms of COVID-19 and hypothesizes that affected patients may be at higher risk of developing cognitive decline after overcoming the primary COVID-19 infection. A structured prospective evaluation should analyze the likelihood, time course, and severity of cognitive impairment following the COVID-19 pandemic.
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Brown Adipose Crosstalk in Tissue Plasticity and Human Metabolism.
Scheele, C, Wolfrum, C
Endocrine reviews. 2020;41(1)
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Brown adipose tissue (BAT) is an important contributor to the regulation of metabolism via cellular communication with organs such as liver, muscle, gut and central nervous system. BAT is important for heat generation and is at high levels in human infants. Levels of activation of BAT decline as we age and it has been shown that the amount of BAT is smaller and its activity reduced in those with obesity and type 2 diabetes. To date, there is no answer to efficiently restore functional BAT in aging and obese subjects. This review looks at experiments done on the factors secreted from active BAT (batokines). The review aims to provide a structure for the processes and cell types involved in BAT and the recent findings of BAT whole-body communication are discussed. Altogether, these findings demonstrate that BAT has an adaptive capacity. Studying batokines, offers an alternative approach to identify novel drug targets for metabolic regulation.
Abstract
Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central nervous system and acute activation increases metabolic rate. Brown adipose tissue (BAT) recruitment occurs during cold acclimation and includes secretion of factors, known as batokines, which target several different cell types within BAT, and promote adipogenesis, angiogenesis, immune cell interactions, and neurite outgrowth. All these processes seem to act in concert to promote an adapted BAT. Recent studies have also provided exciting data on whole body metabolic regulation with a broad spectrum of mechanisms involving BAT crosstalk with liver, skeletal muscle, and gut as well as the central nervous system. These widespread interactions might reflect the property of BAT of switching between an active thermogenic state where energy is highly consumed and drained from the circulation, and the passive thermoneutral state, where energy consumption is turned off. (Endocrine Reviews 41: XXX - XXX, 2020).
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Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target.
Sorgdrager, FJH, Naudé, PJW, Kema, IP, Nollen, EA, Deyn, PP
Frontiers in immunology. 2019;10:2565
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Inflammation is a normal physiological process activated by the immune system in response to injury or infection. As we age, the immune system changes and the balance between pro- and anti-inflammatory agents can shift. This causes a chronic inflammatory state referred to as inflammaging. The rate of inflammaging is strongly associated with age-related disability, disease and mortality. The way in which the essential amino acid tryptophan (Trp) is broken down affects inflammation. If it is converted to kynurenine (Kyn) and its metabolites, inflammation is modulated. Studies have shown that the Kyn/Trp ratio, measured in blood, is strongly associated with ageing in humans. It could therefore be a useful marker to predict the onset of age-related diseases. This review discusses the metabolism of Trp and the links to inflammation. The authors hypothesize how intervening in these pathways could impact health- and lifespan. Future studies are needed to confirm the value of Trp metabolism as a biomarker for (un)healthy ageing and as drug target for inflammaging-related disease.
Abstract
Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD+). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.
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Vitamin D Supplementation in Central Nervous System Demyelinating Disease-Enough Is Enough.
Häusler, D, Weber, MS
International journal of molecular sciences. 2019;20(1)
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Vitamin D is associated with a reduced risk and severity of multiple sclerosis (MS). However, whether supplementing vitamin D level alters disease severity, is a matter of ongoing debate. This review looks at both clinical and pre-clinical evidence for supplementing vitamin D in people with MS. In vitro experiments show that vitamin D and its metabolites can alter function of various immune cells, mostly via interaction with vitamin D receptors (VDR). Results from human clinical trials, however, are mixed. Preclinical evidence suggests that high dose vitamin D supplementation, when leading to hypercalcaemia, a potentially serious side effect of excessive vitamin D intake, may worsen MS. The authors also review research which suggests mechanisms by which sun exposure can improve MS symptoms independent of vitamin D production. The authors conclude that moderate sun exposure, combined with adequate dietary intake of vitamin D, and in conjunction with a regular assessment of vitamin D serum levels (to avoid hypercalcaemia), might be the best strategy for patients with MS.
Abstract
The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS.
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Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Rasa, S, Nora-Krukle, Z, Henning, N, Eliassen, E, Shikova, E, Harrer, T, Scheibenbogen, C, Murovska, M, Prusty, BK
Journal of translational medicine. 2018;16(1):268
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The causes of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are currently unknown, however viruses have been implicated. The absence of well-designed studies has hindered the understanding of this disease and the aim of this review was to discuss the literature regarding viruses and ME/CFS. Several viruses were discussed including the herpes virus, which is responsible for illnesses such as chicken pox and cold sores. This virus has not always been associated with the onset of ME/CFS, however it may be in certain individuals. The enteroviruses, which are responsible for illnesses such as hand, foot and mouth and polio, were also reviewed and it was concluded that it is unlikely that these have a role in ME/CFS. Several other viruses were also discussed. The authors then went on to describe how these viruses can affect human cells, potentially causing ME/CFS. It was concluded that the data available is controversial and only certain individuals may be affected, better studies are required. This study could be used by healthcare professionals to identify individuals at risk of ME/CFS following viral infection and understanding how ME/CFS may develop.
Abstract
BACKGROUND AND MAIN TEXT Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and controversial clinical condition without having established causative factors. Increasing numbers of cases during past decade have created awareness among patients as well as healthcare professionals. Chronic viral infection as a cause of ME/CFS has long been debated. However, lack of large studies involving well-designed patient groups and validated experimental set ups have hindered our knowledge about this disease. Moreover, recent developments regarding molecular mechanism of pathogenesis of various infectious agents cast doubts over validity of several of the past studies. CONCLUSIONS This review aims to compile all the studies done so far to investigate various viral agents that could be associated with ME/CFS. Furthermore, we suggest strategies to better design future studies on the role of viral infections in ME/CFS.
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Therapist-supported Internet cognitive behavioural therapy for anxiety disorders in adults.
Olthuis, JV, Watt, MC, Bailey, K, Hayden, JA, Stewart, SH
The Cochrane database of systematic reviews. 2016;3:CD011565
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Previous research has supported the use of cognitive behavioural therapy (CBT) in the treatment of anxiety disorders, which is aimed at changing negative or unhealthy thinking patterns. Many individuals with anxiety find it challenging to get to CBT appointments and so an internet-based programme, with telephone and email support, has been developed. This systematic review of 38 randomised controlled trial studies aimed to assess the effects of internet CBT (ICBT) on anxiety symptoms and severity. The results showed that there was a clinically important improvement in anxiety alongside reductions in symptom severity and an increase in the patient’s quality of life (QoL) when following ICBT compared to no treatment or online support group discussions. When comparing supported ICBT and self-guided CBT there were no differences between anxiety symptom severity and QoL. When comparing ICBT and face to face therapist-supported CBT, no differences were reported in anxiety symptoms and QoL. It was concluded that ICBT is more beneficial than no treatment or online discussion groups and may be just as useful as face-to-face CBT. The number of studies that compared ICBT to self-guided CBT was limited and so specific conclusions were difficult to ascertain. This study could be used by healthcare professionals to understand that people suffering from anxiety may not be receiving the treatment they need for fears of new situations or leaving the house. In this instance ICBT is an alternative treatment that is just as beneficial as face-to-face therapy.
Abstract
BACKGROUND Cognitive behavioural therapy (CBT) is an evidence-based treatment for anxiety disorders. Many people have difficulty accessing treatment, due to a variety of obstacles. Researchers have therefore explored the possibility of using the Internet to deliver CBT; it is important to ensure the decision to promote such treatment is grounded in high quality evidence. OBJECTIVES To assess the effects of therapist-supported Internet CBT (ICBT) on remission of anxiety disorder diagnosis and reduction of anxiety symptoms in adults as compared to waiting list control, unguided CBT, or face-to-face CBT. Effects of treatment on quality of life and patient satisfaction with the intervention were also assessed. SEARCH METHODS We searched the Cochrane Depression, Anxiety and Neurosis Review Group Specialised Register (CCDANCTR) to 16 March 2015. The CCDANCTR includes relevant randomised controlled trials from MEDLINE, EMBASE, PsycINFO and CENTRAL. We also searched online clinical trial registries and reference lists of included studies. We contacted authors to locate additional trials. SELECTION CRITERIA Each identified study was independently assessed for inclusion by two authors. To be included, studies had to be randomised controlled trials of therapist-supported ICBT compared to a waiting list, attention, information, or online discussion group; unguided CBT (that is, self-help); or face-to-face CBT. We included studies that treated adults with an anxiety disorder (panic disorder, agoraphobia, social phobia, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, obsessive compulsive disorder, and specific phobia) defined according to the Diagnostic and Statistical Manual of Mental Disorders III, III-R, IV, IV-TR or the International Classification of Disesases 9 or 10. DATA COLLECTION AND ANALYSIS Two authors independently assessed the risk of bias of included studies and judged overall study quality. We used data from intention-to-treat analyses wherever possible. We assessed treatment effect for the dichotomous outcome of clinically important improvement in anxiety using a risk ratio (RR) with 95% confidence interval (CI). For disorder-specific and general anxiety symptom measures and quality of life we assessed continuous scores using standardized mean differences (SMD). We examined statistical heterogeneity using the I(2) statistic. MAIN RESULTS We screened 1736 citations and selected 38 studies (3214 participants) for inclusion. The studies examined social phobia (11 trials), panic disorder with or without agoraphobia (8 trials), generalized anxiety disorder (5 trials), post-traumatic stress disorder (2 trials), obsessive compulsive disorder (2 trials), and specific phobia (2 trials). Eight remaining studies included a range of anxiety disorder diagnoses. Studies were conducted in Sweden (18 trials), Australia (14 trials), Switzerland (3 trials), the Netherlands (2 trials), and the USA (1 trial) and investigated a variety of ICBT protocols. Three primary comparisons were identified, therapist-supported ICBT versus waiting list control, therapist-supported versus unguided ICBT, and therapist-supported ICBT versus face-to-face CBT.Low quality evidence from 11 studies (866 participants) contributed to a pooled risk ratio (RR) of 3.75 (95% CI 2.51 to 5.60; I(2) = 50%) for clinically important improvement in anxiety at post-treatment, favouring therapist-supported ICBT over a waiting list, attention, information, or online discussion group only. The SMD for disorder-specific symptoms at post-treatment (28 studies, 2147 participants; SMD -1.06, 95% CI -1.29 to -0.82; I(2) = 83%) and general anxiety symptoms at post-treatment (19 studies, 1496 participants; SMD -0.75, 95% CI -0.98 to -0.52; I(2) = 78%) favoured therapist-supported ICBT; the quality of the evidence for both outcomes was low.One study compared unguided CBT to therapist-supported ICBT for clinically important improvement in anxiety at post-treatment, showing no difference in outcome between treatments (54 participants; very low quality evidence). At post-treatment there were no clear differences between unguided CBT and therapist-supported ICBT for disorder-specific anxiety symptoms (5 studies, 312 participants; SMD -0.22, 95% CI -0.56 to 0.13; I(2) = 58%; very low quality evidence) or general anxiety symptoms (2 studies, 138 participants; SMD 0.28, 95% CI -2.21 to 2.78; I(2) = 0%; very low quality evidence).Compared to face-to-face CBT, therapist-supported ICBT showed no significant differences in clinically important improvement in anxiety at post-treatment (4 studies, 365 participants; RR 1.09, 95% CI 0.89 to 1.34; I(2) = 0%; low quality evidence). There were also no clear differences between face-to-face and therapist supported ICBT for disorder-specific anxiety symptoms at post-treatment (7 studies, 450 participants; SMD 0.06, 95% CI -0.25 to 0.37; I(2) = 60%; low quality evidence) or general anxiety symptoms at post-treatment (5 studies, 317 participants; SMD 0.17, 95% CI -0.35 to 0.69; I(2) = 78%; low quality evidence).Overall, risk of bias in included studies was low or unclear for most domains. However, due to the nature of psychosocial intervention trials, blinding of participants and personnel, and outcome assessment tended to have a high risk of bias. Heterogeneity across a number of the meta-analyses was substantial, some was explained by type of anxiety disorder or may be meta-analytic measurement artefact due to combining many assessment measures. Adverse events were rarely reported. AUTHORS' CONCLUSIONS Therapist-supported ICBT appears to be an efficacious treatment for anxiety in adults. The evidence comparing therapist-supported ICBT to waiting list, attention, information, or online discussion group only control was low to moderate quality, the evidence comparing therapist-supported ICBT to unguided ICBT was very low quality, and comparisons of therapist-supported ICBT to face-to-face CBT were low quality. Further research is needed to better define and measure any potential harms resulting from treatment. These findings suggest that therapist-supported ICBT is more efficacious than a waiting list, attention, information, or online discussion group only control, and that there may not be a significant difference in outcome between unguided CBT and therapist-supported ICBT; however, this latter finding must be interpreted with caution due to imprecision. The evidence suggests that therapist-supported ICBT may not be significantly different from face-to-face CBT in reducing anxiety. Future research should explore heterogeneity among studies which is reducing the quality of the evidence body, involve equivalence trials comparing ICBT and face-to-face CBT, examine the importance of the role of the therapist in ICBT, and include effectiveness trials of ICBT in real-world settings. A timely update to this review is needed given the fast pace of this area of research.
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The stigma of obesity in the general public and its implications for public health - a systematic review.
Sikorski, C, Luppa, M, Kaiser, M, Glaesmer, H, Schomerus, G, König, HH, Riedel-Heller, SG
BMC public health. 2011;11:661
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Obesity rates are still rising and, in addition to co-morbid diseases, perceived discrimination and stigmatisation leads to worse outcomes in obese individuals. The aim of this systematic review, including seven studies, was to investigate how the lay public perceive people with obesity or overweight (stigmatizing attitudes); (b) what they attribute obesity to (causal attribution) and (c) what types of interventions they support. Higher rates of stigmatising attitudes were associated with attributing obesity more to behaviour and less to heredity, lower levels of education and older age of the respondents, and not seeing obesity as an illness. Causal attributions varied slightly from study to study but most found that lack of activity behaviour, overeating and lack of willpower were the most prevalent causal attributions, with more than two thirds of respondents associating these factors to obesity, whilst only about a third agreed to heredity being an important factor. Environmental factors, in particular a bad food environment, was seen as a possible factor in obesity by about half of the respondents. In terms of prevention efforts, support was highest for childhood prevention and information campaigns, followed by banning junk foods in schools and banning junk food advertising, whilst taxation of unhealthy foods received the least support.
Abstract
BACKGROUND Up to this date, prevalence rates of obesity are still rising. Aside from co-morbid diseases, perceived discrimination and stigmatization leads to worsen outcomes in obese individuals. Higher stigmatizing attitudes towards obese individuals may also result in less support of preventive and interventive measures. In light of the immense burden of obesity on health care systems and also on the individuals' quality of life, accepted and subsidized preventive measures are needed. Policy support might be determined by views of the lay public on causes of obesity and resulting weight stigma. This study seeks to answer how representative samples of the lay public perceive people with obesity or overweight status (stigmatizing attitudes); what these samples attribute obesity to (causal attribution) and what types of interventions are supported by the lay public and which factors determine that support (prevention support). METHODS A systematic literature search was conducted. All studies of representative samples reporting results on (a) stigmatizing attitudes towards overweight and obese individuals, (b) causal beliefs and (c) prevention support were included. RESULTS Only 7 articles were found. One study reported prevalence rates of stigmatizing attitudes. About a quarter of the population in Germany displayed definite stigmatizing attitudes. Other studies reported causal attributions. While external influences on weight are considered as well, it seems that internal factors are rated to be of higher importance. Across the studies found, regulative prevention is supported by about half of the population, while childhood prevention has highest approval rates. Results on sociodemographic determinants differ substantially. CONCLUSIONS Further research on public attitudes toward and perception of overweight and obesity is urgently needed to depict the prevailing degree of stigmatization. Introducing a multidimensional concept of the etiology of obesity to the lay public might be a starting point in stigma reduction.