key: cord-0874041-552bc09v
authors: Sukocheva, Olga A.; Maksoud, Rebekah; Beeraka, Narasimha M.; Madhunapantula, SabbaRao V.; Sinelnikov, Mikhail; Nikolenko, Vladimir N.; Neganova, Margarita E.; Klochkov, Sergey G.; Amjad Kamal, Mohammad; Marshall-Gradisnik, Sonya; Staines, Donald R
title: Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome
date: 2021-11-26
journal: J Adv Res
DOI: 10.1016/j.jare.2021.11.013
sha: 1651c220e129263b3d160a22711950f16448e7df
doc_id: 874041
cord_uid: 552bc09v

BACKGROUND: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) triggers the development of numerous pathologies and infection-linked complications and exacerbates existing pathologies in nearly all body systems. Aside from the primarily targeted respiratory organs, adverse SARS-CoV-2 effects were observed in nervous, cardiovascular, gastrointestinal/metabolic, immune, and other systems in COVID-19 survivors. Long-term effects of this viral infection have been recently observed and represent distressing sequelae recognised by the World Health Organisation (WHO) as a distinct clinical entity defined as post-COVID-19 condition. Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). AIMS OF REVIEW: In this study, COVID-19 clinical presentation and associated post-infection sequelae (post-COVID-19 condition) were reviewed and compared with ME/CFS symptomatology. KEY SCIENTIFIC CONCEPTS OF REVIEW: The onset, progression, and symptom profile of post COVID-19 condition patients have considerable overlap with ME/CFS. Considering the large scope and range of pro-inflammatory effects of this virus, it is reasonable to expect development of post COVID-19 clinical complications in a proportion of the affected population. There are reports of a later debilitating syndrome onset three months post COVID-19 infection (often described as long-COVID-19), marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnoea. Acute inflammation, oxidative stress, and increased levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), have been reported in SARS-CoV-2 infected patients. Longitudinal monitoring of post COVID-19 patients is warranted to understand the long-term effects of SARS-CoV-2 infection and the pathomechanism of post COVID-19 condition.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), defined as coronavirus disease of 2019 (COVID- 19) , has caused a viral pandemic emergency of international concern. Public health services registered over 249 million SARS-CoV-2 infections and nearly five million associated deaths worldwide on 25 October 2021 [1] . The majority of those infected with COVID-19 demonstrate mild flu-like symptoms. However, a subset of COVID-19 patients developed severe pathology including bilateral interstitial pneumonitis and acute respiratory distress syndrome (ARDS), with a mortality rate of over 50% [2, 3] . Although the virus primarily affects the respiratory organs [2] , SARS-CoV-2 pathogens were shown to impact metabolism and multiple organs and systems, including the cardiovascular [3, 4, 5] , gastrointestinal [4] , and nervous systems [6, 7] (Figure 1 ). The proportion of the affected population is constantly growing as the pandemic is ongoing and is accompanied by large variety of symptoms with various duration. The number of patients with serious post-COVID complications is of great concern. For instance, persistence of dyspnoea and neuropsychological symptoms were registered in 35% of non-hospitalized and 87% of hospitalized COVID-19 patients [5, 6] .

Recent reports indicated that several months after acute SARS-CoV-2 infection, some patients were still experiencing severe fatigue and other systemic symptoms described as long-COVID [7, 8] . Symptoms that persist for longer than three weeks have been classified as "postacute COVID-19", and those that persist beyond 12 weeks as "chronic COVID-19" [9] . The WHO guidelines now describe a post COVID-19 condition which occurs three months post-SARS-CoV-2 infection [10] . The onset is suggested to be independent of initial infection severity, pre-existing conditions, or age [11] . Some studies, however, have reported a greater amount of post-viral symptoms in more severe and critically ill patients [12] . A hospital-based study of 143 COVID-19 patients registered debilitating fatigue in 53% of survivors approximately two months after discharge from the hospital in Rome, Italy [6] . Another study in China observed that 16% of COVID-19 patients experienced weakening fatigue and 25% suffered aberrant lung function three months after discharge from the intensive care unit (ICU) [13] . A longitudinal study on non-hospitalised COVID-19 patients found that symptoms such as loss of smell, loss of taste, fatigue, or shortness of breath were most commonly reported four and seven months after SARS-CoV-2 infection [14] . Another report indicated that 1-3% of post COVID-19 condition patients were found to have symptoms that persisted longer than 12 weeks [11] . Larger controlled studies should confirm the observed symptoms and percentages mentioned above. However, the reported prolonged pathological post-viral condition may represent or closely relate to a range of diseases including myalgic encephalitis/chronic fatigue syndrome (ME/CFS) or other post-infection sequelae. Post-viral and multifactorial aetiology of ME/CFS revealed neuroimmune roots of the illness [15] , which may be compared with post COVID-19 conditions.

This study will review current key signs and symptoms of post-COVID-19 condition, discuss nervous, cardiovascular, gastrointestinal/metabolic, immune, and other systems and potential overlap with ME/CFS, and suggest directions for relevant interventions in COVID- 19 survivors. Considering that SARS-CoV-2 effects and host-related consequences are highly heterogenous, multiple mechanisms of post COVID-19 complications will be discussed with an accent in the most relevant ME/CFS-related targets.

Several studies of the first SARS pandemic (2003) indicated that 60% of study participants complained of unresolved health problems including fatigue after being infected with the coronavirus [16] [17] [18] [19] . When interviewed four years after the acute infection phase, 40% of the SARS (2003) infection survivors in Hong Kong complained of ongoing fatigue and other complications [17, 18] . SARS survivors reported diffuse muscle pain, various symptoms of depression, muscle weakness, and sleep-related abnormalities, defined as chronic post-SARS syndrome [19] . Post-SARS patients in Canada reported feeling unfit to work 1-3 years after infection due to various symptoms including persistent fatigue [19] . Other studies that monitored SARS survivors also reported a 40% rate of chronic fatigue development and associated social stigmatization [18, 20] . However, many facets of first SARS infection were not investigated. Only a few studies investigated the mechanism of post-infection sequelae resulting in inconclusive outcomes [13] .

Regarding the current SARS-CoV-2 pandemic, the number of COVID-19 patients is growing, however, many have not completely recovered [5-8, 11, 21] . Post condition follow-up studies were initiated primarily for those patients who were hospitalized with the most severe infection and spent on average two weeks at an intensive care unit (ICU).

The follow-up data indicated serious consequences in a large number of the patients [6, 13, 22] . Persistent functional disabilities (including fatigue) long after ICU discharge were reported [23] . In a study conducted by Freitag et al, 45 .2% of COVID-19 patients subsequently met symptom-specific ME/CFS criteria six months post-infection [24] . In a large study (across 56 countries) comprising 3,762 COVID-19 patients with persisting symptoms, 56.8% of participants reported post-exertional malaise (PEM), one of the major ME/CFS symptoms [25] .

Post COVID-19 condition has been recently described as having considerable overlap of symptoms with ME/CFS [26] . ME/CFS is a complex illness marked by persistent fatigue that is unrelieved by rest in combination with a range of other debilitating symptoms such as autonomic disturbances, endocrine dysfunction, and impaired cellular energy metabolism and ion transport [27] .

Symptom presentation varies from patient to patient, ranging from mild to severe, with approximately 25% of ME/CFS patients being bedbound [28] . Many factors were shown to influence development of fatigue which was also linked to multiple intracellular mechanisms indicating a heterogeneity of this illness. Biochemical determinants of fatigue were often associated with immunopathogenesis and metabolic abnormalities [29] . Debilitating fatigue has often been marked by chronic muscle weakness and pain [30] . Viral and bacterial infections have been shown to trigger development of ME/CFS [20, 31] . Development of ME/CFS has been associated with Epstein-Barr virus (EBV) [32, 33] , human herpesviruses (HHV-6, HHV-7, HHV-8) [34] [35] [36] , cytomegalovirus (CMV) [37] , human parvovirus B19 (B19V), lentivirus [33] , and enterovirus infections [38] . The absence of targeted treatment and molecular-based diagnostic tools for this disease are attributed to the heterogeneity and unclear molecular mechanisms of ME/CFS. Diagnosis for this disease is derived using symptom-specific case criteria [27, 39, 40] , including presence of post-exertional malaise (PEM) [41] .

3. SARS-CoV-2: the mechanism of virus ACE receptor-mediated effects with links to ME/CFS SARS-CoV-2 consists of a single linear RNA molecule which is ≈ 89 % identical to previously detected bat SARS-like-CoVZXC21 and ≈ 82 % identical to human SARS-CoV [42] . The virus belongs to the large family of coronaviruses and includes viral envelopestabilizing components: S (spike; angiotensin converting enzyme 2 (ACE2)-interacting protein), E (envelope), M (membrane proteins), and N (nucleocapsid protein). Moreover, SARS-CoV-2 yields virulence factors (non-structural proteins) that can manipulate the host immune system and cell physiology [42, 43] . The mechanism of interactions between the host immune system and SARS-CoV-2 (pathogenesis) remains largely unclear. However, it has been documented that SARS-CoV-2 affects the host immune system resulting in a variety of clinical COVID-19 symptoms, ranging from asymptomatic to severe complications [44] . One of the confirmed COVID-19 systemic responses is a strong and disproportionate immune reaction to SARS-CoV-2 particles. The virus stimulates avalanche-like increases in proinflammatory cytokines, including IL-6 and TNF (Table 1) [45] [46] [47] . Multiple recent studies reported that SARS-CoV-2 severity is associated with "cytokine storm", the out-of-control cytokine cascades produced by the host immune system after the introduction of the viral particles [8, 48, 49] .

SARS-CoV-2 has been shown to preferentially infect cells with higher expression of the virus spike protein-binding ACE2 receptor [50] . The penetration of the virus into cells starts with ACE2 binding, internalization of the ACE2-virus, and ACE2 shedding by tumour necrosis factor α (TNFα) convertase, a disintegrin and metalloprotease 17 (ADAM17) [51] . Activated ADAM17 signalling has been reported to disrupt biological barriers, cause endothelial senescence, and induce aging-associated brain pathologies [52, 53] . The hypothesis of involvement of ADAM17 in development of post-COVID-19 syndrome was recently reviewed [54] . Soluble human ACE2 was shown to inhibit SARS-CoV-2 infection in human blood vessel and kidney organoids [55, 56] . Consequently, several trials tested pathological influence of ACE2 gene single nucleotide polymorphisms (SNPs) [57, 58] . COVID-19-related morbidity and mortality were linked to D allele frequency of ACE2 [59, 60] . Multiple ACE2 variants were identified, suggesting ACE Del/Del polymorphisms influence COVID-19 susceptibility and facilitate development of a more aggressive infection profile [56, 61] . Accordingly, ACE Del/Del polymorphisms may be associated with post-COVID-19 condition onset. ACE2 polymorphisms may act as a predictive biomarker of ME/CFS. A study that previously tested association between ACE polymorphism and ME/CFS was published in 2009 and used a diathesis-allostatic load (AL) model [62] to assess pathological stress-related symptoms including ME/CFS [63] . Notably, high AL scoring was associated with ACE T allele rs4968591 and TT genotype was more common in subjects with high AL in ME/CFS. ME/CFS participants with TT genotype had the highest median C-reactive protein (CRP) levels, lowest urinary cortisol level (females), and increasing linear trend in IL-6 [63] . Considering that ACE2 polymorphism is associated with cytokine storm and COVID-19 severity [64] , further investigations would be necessary to identify whether the ACE2 polymorphism correlates with onset and development of ME/CFS.

Immune system is responsible for the recognition of viral particles and their elimination.

Previous research has indicated that SARS-CoV-2 may predominantly infect macrophages (innate immunity cell effectors), although this assumption requires experimental confirmation and is currently based on previous findings for the SARS-CoV strain which was shown to infect alveolar epithelial cells, vascular endothelial cells, and macrophages [65] . Macrophages, dendritic cells, and neutrophils provide the initial immune defence barrier alongside airway mucosa. Encountering infection, macrophages can trigger anti-viral immune reactions and define the intensity of immune response. Elevated levels of macrophages and their overactivation were detected in severe cases of COVID-19 (Table 1) [66, 67] . Macrophages that express ACE2 (the virus-binding protein) along with incorporated SARS-CoV-2 nucleoprotein antigen were shown to infiltrate the spleen and lymph nodes in COVID-19 patients [68] .

Infiltrating monocytes/macrophages and neutrophils express virus-recognizing receptors and can identify viruses and virus-infected cells. The virus is then recognized by cytosol-located pathogen recognition receptors (PRRs) after viral RNA enters its reproductive cycle, duplicates, and becomes double-stranded [69] . Coronaviruses, including SARS-CoV-2, encode specific proteins that can prevent PRR-mediated detection and activation of anti-viral mechanisms [70] . Accordingly, alveolar macrophages and monocytes were indicated as the original source of cytokines associated with abnormal systemic responses and multiple organ dysfunction in COVID-19 patients [70] . Previous studies have indicated that coronaviruses inhibit interferon (INF)-based responses and/or viral RNA identification by pathogenassociated molecular pattern (PAMP) receptors [71] . In contrast to the previous SARS strain, SARS-CoV-2-linked over-production of cytokines indicates effective recognition of the virus by the immune system [8, 48] . It is possible that Toll-like receptor 3 (TLR-3) may be able to identify SARS-CoV-2 [49, 72] . However, the mechanisms of this potential interaction have not yet been experimentally tested. Following the virus-sensing process, immune cells start to produce large amounts of pro-inflammatory cytokines and ROS, which are necessary for the propagation of defensive responses and elimination of viral particles. The key immunepathologies related to ME/CFS and COVID-19 are presented in Table 1 .

Many T-cell activating cytokines can be produced by macrophages. The level of produced cytokines in an immune response should be balanced to avoid tissue damage.

Cytokine storm was registered during severe clinical manifestations of COVID-19 [8, 48] .

SARS-CoV-2 infected macrophages have been shown to produce excessive amounts of interleukin-6 (IL-6) and IL-1, contributing to extreme inflammation in COVID-19 patients [68] . High IL-6 serum levels were detected in > 50% of the COVID-19 patients [73] . The progression of disease severity was marked by the macrophage over-reactivity defined as macrophage activation syndrome (MAS) [48, 68] . Presence of MAS in adult COVID-19 patients with ARDS is indicated by high CRP levels in serum, which are not commonly observed during viral infections. McGonagle et al suggested a new MAS classification that can be used to uncover the role of macrophages in the progression of COVID-19-induced pneumonia towards ARDS [48] .

The overproduction of pro-inflammatory cytokines in some patients with COVID-19 resulted in cardiovascular complications, multiple organ dysfunctions, and is considered lethal [74, 75] . Along with IL-6, enhanced production of T helper type-1 and type-2 (Th1 and Th2) cytokines (galectins, tumour necrosis factor alpha (TNF), interferon-γ (INF), IL-2, and IL-17) was detected in COVID-19 patients [76, 77] . This increase in pro-inflammatory cytokines was also linked to subsequent T-cell exhaustion and PD-1 upregulation [78, 79] . Many recent studies have detected higher levels of IL-6 and IL-10 in patients with severe COVID-19 [4, 76, 77] . Notably, high IL-6 was determined to be a lethal risk factor in SARS-CoV-2 infected patients [80] . Therefore, IL-6 was named as a potential therapeutic target in SARS-CoV-2infected patients. Tocilizumab (anti-IL-6 receptor monoclonal antibody) was tested for minimizing inflammation, with promising results [81] . The suggestion was supported by Ruan et al, who demonstrated a significant difference in serum IL-6 levels between COVID-19 survivors and non-survivors [77] . However, another study detected no association among various routine laboratory markers of inflammation (leukocyte, neutrophil, and lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), CRP) and fatigue scores [82] . The study also found no association between fatigue scores and serum levels of IL-6 or soluble CD25, although the relatively small sample size of the study (128 participants) should be noted [82] .

Abnormal immune system signalling was previously associated with debilitating fatigue [83] [84] [85] and fibromyalgia [86] . Changes in cytokine levels have been reported in ME/CFS patients [84, 86, 87] . A study published by Hornig et al. reported that early in the onset of the illness, the immune system of ME/CFS patients produces both disbalanced proportions of pro-and anti-inflammatory cytokines [83] . A recent systematic review indicated that cytokines may have ambiguous roles in ME/CFS [88] , supporting the hypothesis that this illness is highly heterogeneous. The dynamic changes in ME/CFS cytokine profile require longitudinal investigations as the illness progresses [89] .

The link between high levels of IL-6 (and other pro-inflammatory cytokines) and the development of post-COVID-19 symptoms, including fatigue and/or related sequelae, remains to be confirmed. However, the contribution of immune disbalances towards development of chronic fatigue is supported by several post-infection ME/CFS studies that analysed post-viral complications [20, 32, 35, 39, 41] . The wide scope of ME/CFS-associated pathologies supports the assumption that ME/CFS is a multifactorial illness with diverse molecular backgrounds.

The pathomechanism of ME/CFS development is complex, where the majority of studies indicated immunological changes, including modest systemic inflammation [15, 90] , significant reduction of Natural Killer (NK) cell function [91, 92] , altered B cell phenotypes [93] , significant changes in the level of circulating cytokines, including IL-1 (IL-1α and IL-1β), IL-6 [88, 94] , and TNF . However, the cellular mechanisms of innate immune system responses, their role in potentially precipitating fatigue, and their therapeutic potential are yet to be examined in current and recovered COVID-19 patients.

Immune cell phenotypes were found to be significantly different between severe and non-severe COVID-19 patients. Higher NK cell numbers were found in peripheral blood and were associated with higher clearance rate of the virus and testing negative for COVID-19.

Conversely, patients with lower NK cell numbers had presented longer duration of viral shedding and the significantly lower survival outcomes in the lymphocytopenia group [96] .

Interestingly, the only consistently reported finding in ME/CFS patients is significantly reduced NK cell function [92] .

Susceptibility to SARS-CoV-2 is defined by individual immune system characteristics, as the virus has been shown to affect both innate and adaptive immune responses [48, [72] [73] [74] [75] [76] [77] .

Asymptomatic COVID-19 disease resolution relies on anti-viral adaptive immune responses that can naturally eliminate SARS-CoV-2 virus particles in the majority of infected people [97, 98] . The adaptive T-cell responses are activated during acute and progressive infection stages and mediated by CD8+ T cells, which are key effectors for acute infection eradication and lifelong protective immunity [97] . T-cell-activating cytokines, together with antigenic signals, are necessary for differentiation and clonal expansion of the naïve T cells [99] . However, in some circumstances (often unknown) the viral effects were associated with over-activation or reduction in immune responses in some patients. The dysfunctional reactivity Overwhelming increases in the production of these cytokines can be devastating for viral control and facilitate development of faulty CD8+ T-cells, described as exhausted T-cells [97, 100] . Commonly, during chronic viral infections, prolonged viral antigen exposure, and/or excessive inflammation (overproduction of cytokines/cytokine storm), CD8+ T-cells develop the exhausted phenotype, marked by limited capacity to eliminate viral pathogens [100, 102] .

Exhausted T-cells express ensembles of inhibitory receptors and fail to accomplish their key anti-viral functions [97, 100] . The exhausted T-cell phenotype was reported in severe COVID-19 patients [79] . Cytotoxic CD8+ T-cells in COVID-19 patients are activated by proinflammatory cytokines and display functional exhaustion characteristics including expression of CD94/NK group 2 member A receptor (NKG2A), programmed cell death protein 1 (PD-1),

and T-cell immunoglobulin and mucin domain 3 (TIM-3) [78] .

Aside from signs of T-cell exhaustion, SARS-CoV-2 was shown to downregulate the production of interferons (including INF IL-2, and granzyme B) and slow down immune responses [49, 103] . General T cell degeneration was also marked by lymph node and spleen atrophy, as well as a decreased number of CD8+ T-cells in severe COVID-19 patients [104] .

Inhibition of T-cell-mediated immune responses was linked to downregulation of MHC class I and II molecules and problems with antigen presentation [49] . CD8+ T-cell abnormality was associated with decreased CD107a externalization [103] . However, a link between T-cell exhaustion and development of post-COVID-19 illness requires confirmation. Immune cells from ME/CFS patients were not checked for presentation of exhausted phenotype markers either.

The relatively slow initial progression of immune responses was also identified as one of the immune-system-based defects in severe COVID-19 cases [43] . A potential problem with circulating memory T and B cells was suggested as being responsible for the initial low rate of anti-viral responses [105] . A lower level of memory CD4 + T-cells contributed to poorer T cell responses in SARS patients [106] . Currently, there is limited information about memory B-cell kinetics in COVID-19 patients. To the best of our knowledge, B-cell kinetics in association with development of ME/CFS as a post-viral complication has not yet been investigated.

The presence of autoantibodies has been described in COVID-19 patients [107] . The autoantibodies were detected using the rapid extracellular antigen profiling method, which indicated increased auto-responses in COVID-19 patients compared to healthy controls.

Autoantibodies were also systemically found throughout various tissues and implicated in the development of post COVID-19 condition. However, it remains to be determined whether these autoantibodies persist beyond the acute infection phase of COVID-19 and whether they are casually associated with post COVID-19 condition [107] . Arthur et al detected presence of ACE2-specific autoantibodies in many post COVID patients [108] . Consequently, patients with post-acute sequelae were found to have lower activity of soluble ACE2 in blood plasma and increased circulation of angiotensin II which may lead to enhanced proinflammatory state in post COVID-19 patients [108] .

Another study indicated the presence of active G-protein coupled receptors (GPCR)targeting autoantibodies, including β2-and α1-adrenoreceptors, angiotensin-II AT1-receptors, and muscarinic M2-receptors in post COVID-19 condition patients [109] . Using lumbar puncture, Franke et al assessed autoantibody levels in cerebrospinal fluids (CSF) from eleven severe COVID-19 patients (median age 67, 8 male) with unclear aetiology neurological symptoms diagnosed after admission to ICU and onset of respiratory complications [110] . The study analysis addressed antigen binding to a large panel of intracellular and surface antigen markers for CNS diseases, including antibodies against amphiphysin, Delta/Notch -like EGF repeat containing receptor, collapsin response-mediator protein-5, glutamic acid decarboxylase 65-kilodalton isoform, cardiolipin, beta2-glycoprotein/annexin/glutamate receptors, dipeptidyl-peptidase-like protein 6, γ-aminobutyric acid type A receptors, GPCRs for gammaaminobutyric acid receptors, metabotropic glutamate receptor, leucine-rich glioma-inactivated 1 protein, contactin-associated protein-like 2, dopamine-2 receptor, aquaporin-4, myelin, and skeletal muscle proteins [110] . The collected data indicated elevated level of autoantibodies affecting specific brain targets, although the comparison was not impeccable as control CSF samples were not collected in patients without neurological illness. Despite this limitation, the authors suggested the development of neurological pathologies as contributing factor to the severity of the illness [110] . It was indicated that generation of autoantibodies may initiate and/or impact multi-organ pathologies in COVID-19. Accordingly, the development of targeted immunotherapies was indicated as a potential therapeutic approach for affected COVID-19 patients. Whether such autoreactivity can cause persisting neurological morbidity after clearance of SARS-CoV-2 and remission of COVID-19 requires further studies [110] .

In a prospective study, Virhammar et al investigated 19 mild to critical COVID-19 patients with neurological symptoms [111] . Extensive analysis of CSF content, including measurement of CNS injury biomarkers (neurofilament light chain protein (NFLP), glial fibrillary acidic protein (GFAP), and total tau), was performed and correlated to neurological features and the disease severity. Elevated levels of NFLP, GFAP, and total tau in CSF were found in COVID-19 patients with neurological symptoms [111] . Conclusively, autoimmunity mechanisms may play a role in development of COVID-19-associated pathologies, however, studies have been limited by small sample sizes and lack of suitable controls. Previously, autoantibody levels were found to be elevated in ME/CFS patients [112, 113] . Aptamer BC 007 [114, 115] , an autoantibody blocker against GPCRs has also been assessed for efficacy in "long COVID-19" patients in an initial treatment trial comprising two patients. BC 007 is currently being investigated in a bigger placebo-controlled clinical trial called reCOVer [114, 115] . However, the role of autoimmune antibodies in the development of post COVID condition requires further investigation.

Significantly increased levels of autoantibodies to beta-adrenergic and muscarinic cholinergic receptors were found in a cohort of ME/CFS patients in Sweden, although the pathomechanism of the autoantibody contribution to the development of in ME/CFS is unknown [116] .

Energy metabolism and oxidative processes in mitochondria have been shown to influence innate and adaptive immune responses to SARS-CoV-2 [117, 118] . Mitochondria are the organelles responsible for structural and functional support of oxidative phosphorylation (OXPHOS), intracellular energy metabolism, and homeostasis. Consequently, dysbalanced mitochondrial functions have been suggested to result in immune cell failure and dangerous progression of COVID-19 [119] . Mitochondrial mutations and modified OXPHOS were associated with the development of numerous age-associated pathologies, muscle degeneration, fatigue, and metabolic transformations [47] , which have been reported to contribute to the severity of COVID-19 [3, 120] .

Bidirectional connections were observed between inflammatory signalling and energy metabolism. Abnormal mitochondrial functions and oxidative stress may be activated by inflammation and pro-inflammatory cytokines [121] . Viral infection strongly impacts energy supply and dysregulates metabolism in many tissues, including circulating immune cells [122] [123] [124] . Increased IL-6 was also associated with disbalanced OXPHOS and lowered levels of ATP [123] . Insufficient energy/ATP supply compromises the ability of T-cells to proliferate and function as anti-viral effectors [125, 126] . ROS and metabolic starvation contribute to Tcell exhaustion [127] . Aside from direct activation of apoptosis, oxidative stress and ROS can impact gene activation via epigenetic mechanisms and transform T-cell differentiation towards the exhausted phenotype [102, 128] .

Adaptive antigen-specific responses rely on balanced mitochondrial activity, which is significantly transformed during T-cell activation. A minimal amount of nutrients is required for basal glycolytic rate and effective OXPHOS process in naïve and resting T-cells, which are described as "metabolically quiescent". T-cell receptor (TCR) stimulation triggers a 'glycolytic switch' towards greater utilization of ATP generated via OXPHOS [129] . More differentiated CD8+ memory T-cells were found to have more mitochondrial mass, which provides them with a metabolic advantage and higher reactivity compared to naïve CD8+ T-cells [130] .

Additionally, differentiated and/or activated CD8+ T-cells start to utilize glycolysis to support their anti-viral effector functions [131] . Stimulation of glycolysis in CD8+ T-cells is mediated by Akt and mTOR signalling, which is downregulated during chronic infection and in exhausted T-cells [132] . Suppressed mTOR activity in T-cells is marked by mitochondrial depolarization, lowered mitochondrial biogenesis, and enhanced ROS production [100] . The process of metabolic reprogramming was observed in T-cell subpopulations after acute viral infection [132] . [126] .

Depolarized mitochondria with transformed mitochondrial ultrastructure were detected in those PBMCs. The abnormality was marked by high levels of inflammatory cytokines [126] .

In both COVID-19 and ME/CFS patients, serious tissue and organ damage was associated with increased reactive oxygen species (ROS) formation, which follows the disbalanced cytokine production [133, 134] . Pro-inflammatory cytokines, dysregulated T-cell signalling, abnormal mitochondrial OXPHOS, and elevated level of ROS (oxidative stress) may facilitate development of ME/CFS [135, 136] . High serum TNFα content in patients with ME/CFS was shown to downregulate mitochondrial and cellular bioenergetics [95, 137] .

TNFα-induced signalling through death receptors activates production of ROS, which were shown to be responsible for the destruction of mitochondrial DNA (mtDNA) [138] . Cytokineinduced destruction of mitochondrial signalling was suggested in ME/CFS [95, 137] . However, further investigations are warranted.

Circulating platelets (non-nucleated cells) contain mitochondria, which influence the pro-thrombotic function of these cells. Dis-regulated OXPHOS leads to activation of apoptosis in platelets, which triggers coagulation cascades and aggravates blood clotting and thrombosis [139] . SARS-CoV-2 pathogenesis was associated with increased incidence of thrombosis and lower survival in susceptible patients [140, 141] . The role of platelets and thrombosis-related factors in ME/CFS and other post-viral complications remains largely unclear, although there are indications of transformed coagulation in ME/CFS patients [87] .

The role of mitochondrial pathways in ME/CFS pathogenesis has been explored in several clinical studies and critically assessed in a systematic review conducted by Holden et al [142] . Despite the described mitochondrial changes in ME/CFS patients, the role of mitochondria in development of ME/CFS pathology remains unclear [142] . The long-term changes in mitochondrial and cellular bioenergetics in post COVID-19 condition patients have not yet been reported.

Genetic screening has indicated that several single nucleotide polymorphisms (SNPs) of transient receptor potential (TRP) ion channel family members are commonly exhibited by ME/CFS patients compared to healthy controls [143] . TRP ion channels are membrane bound proteins that are non-selectively permeable to various essential ions including calcium, magnesium, sodium, and zinc. TRPs mediate responses to stress factors associated with environmental changes including fluctuations in temperature, pressure, and chemical and pathogen-related (bacterial and viral infections) exposures [144] . Specifically, several SNPs were detected in the TRP melastatin 3 (TRPM3) group [143, 145] . TRPM3 expression is decreased in NK cells in ME/CFS patients, resulting in impaired Ca 2+ influx [143, 145] .

Bousquet et al discussed the potential involvement of TRP ankyrin A1 (TRPA1) and TRP vanilloid (TRPV1) channels in COVID-19 pathology [146] . TRPV4 has been associated with lung oedema, a frequent symptom in critically ill COVID-19 patients. TRPV4-facilitated ion transport has been shown to disrupt alveolo-capillary barrier integrity. Accordingly, desensitization and/or inhibition of these channels by specific antagonists, including GSK2798745, have shown promising results in treatment of chronic cough or cardiogenic lung oedema patients in phase I clinical trial [147] . However, the role of these channels has not been assessed in post-COVID-19 condition. It remains to test whether TRP expression levels is changed in patients with post-COVID-19 complications. Genetic screening of post COVID-19 condition patients may offer insights about gene signatures and molecular pathways involved in the pathomechanism of this illness.

Importantly, Ca 2+ channels and associated ion signalling pathways are involved in the regulation of numerous processes, including energy metabolism and OXPHOS, cytokine effects, and immune responses [148] . Lower levels of Ca 2+ were detected in COVID-19 patient serum samples [149] . The observed data suggests that low serum Ca 2+ may be an indicator of higher COVID-19 severity. In mild and moderate COVID-19 patients, low Ca 2+ levels correlated to severe multi-organ injuries and changes in IL-6 levels [149] . Hypocalcaemia (low Ca 2+ levels), however, has also been associated with activation of host defence mechanisms [150] . It has been suggested that the SARS-CoV-2 virus utilizes host Ca 2+ channels to facilitate cell entry and efficient replication (virulence) [150] . Given Ca 2+ is a critical regulator of many cellular pathways, including oxidative stress and NK cell cytotoxicity, irregular Ca 2+ levels may have systemic consequences. Long-term involvement of Ca 2+ transport in post COVID- 19 pathology has yet to be investigated. Considerable Ca 2+ dysregulation in ME/CFS and the potential overlap with pathomechanism of post COVID-19 condition remains to be confirmed.

Persistence of dyspnoea and neuropsychological symptoms were registered in 35% of non-hospitalized and 87% of hospitalized COVID-19 patients [5, 6] . In a three-month followup study, 55% of COVID-19 patients had neurological symptoms [151] . These characteristics included higher bilateral gray matter volumes (GMVs) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus, and right cingulate gyrus. Global mean diffusivity of white matter and GMV in the aforementioned regions were correlated with memory loss. GMVs in the right cingulate gyrus and left hippocampus were correlated with the loss of smell [151] . Neurological manifestations have also been described in children infected by SARS-CoV-2 [152] . The most frequent observation found was postinfectious immune-mediated encephalomyelitis-like changes of the brain, which were found in 16 out of 38 child patients. Neural enhancement and myelitis were also observed in 13 and 8 patients (out of 38), respectively [152] . The same study reported splenial legions and myositis associated with multisystem inflammatory post-COVID-19 syndrome [152] . [153] , a highly precise visual tool used frequently in oncological settings and commonly applied in inflammatory conditions of the CNS. Patients included in this study exhibited brain hypometabolism in the right parahippocampal gyrus and thalamus. Changes in metabolism were also observed in other regions of the body, which suggests the systemic nature of this illness. Hypometabolism was associated with persistent anosmia/ageusia, fatigue, and vascular complications [153] . CNSlinked pathologies may be caused by viral particle accumulation in cerebrospinal fluids.

proteins concentrated at the brainstem [140] . SARS-CoV-2 has shown an involuntary growthorienting response to the brainstem due to the presence of high ACE2 receptor levels in this organ compared to other brain regions. A significant part of the assessed post-COVID patient samples (67%) had SARS-CoV-2 RNA and spike proteins located in the olfactory mucosalneuronal junction. Inflammatory responses, neurodegeneration, and viral invasion in brainstem have been described [154] .

Another report described SARS-CoV-2-caused neuroinflammation [155] .

Proinflammatory changes in cerebral fluid composition were shown to provoke cognitive dysfunction, impact sleep-wake cycles, and contribute symptoms of fatigue [156, 157] .

Accordingly, IL-6 has been indicated as a potential mediator of long-term neuropsychiatric symptoms in COVID-19 survivors [158] . Linked to inflammation, psychiatric sequelae have also been described in COVID-19 patients [12, 159] . In a study conducted by Mazza et al., 402 recovered COVID-19 patients were assessed for the presence of psychological changes after COVID-19 and 56% of the participants were scored with the psychiatric pathologies [159] . It has been suggested that these psychopathologies may be fostered directly via viral infection of the CNS or through dysfunctional immune processes such as neuroinflammation as well as disruption of the blood-brain barrier and/or hypothalamic-pituitary adrenal axis [159] . Stigma, social isolation, and other stressors may also contribute to these symptoms [159] . A longitudinal study by Jason et al reported that some post COVID condition patients experienced progressive worsening of neurocognitive symptoms over time [160] .

Among other inflammation-related symptoms, fatigue was found to be the most common symptom (46.9%) among 130 surveyed COVID-19 patients [161] . Significant age difference was detected between patients with fatigue (53.9 ± 13.5 years) compared with those without fatigue (48.5 ± 13.3 years). Patients with fatigue were also hospitalized for longer periods, although no association was observed between the disease severity and presence of fatigue [161] . However, after adjustments for the relevant criteria (defined by the Institute of Medicine as "systemic exertion intolerance disease" characteristics), only 13% patients in this cohort were diagnosed with ME/CFS, indicating that the observed clinical symptoms overlap with ME/CFS in a set of post COVID-19 condition patients [161] .

Nervous system abnormalities have been reported in ME/CFS patients, although the pathomechanism remains unclear. ME/CFS is considered a neurological disorder by the WHO [162] . Infection of microglia, changes in cerebral blood flow, and gray and white matter volumes have been described in ME/CFS patients [163, 164] . Brainstem abnormalities have also been reported, including changes in brainstem functional connectivity [165] . These cognitive impairments may result in brain fog and restless sleep [166] . In conclusion, the observed post-COVID-19 nervous system pathophysiology indicates a potential predisposition to develop ME/CFS. In contrast to the described observations, Sykes et al reported the lack of correlation between symptom burden and radiographic or biochemical abnormalities in brain [167] .

Accordingly, it has been suggested that symptoms may be attributable to biopsychosocial effects of COVID-19. This study, however, included a limited number of tests [167] that may have overlooked clinical characteristics of post COVID-19 condition described above.

Several inflammation-linked cardiovascular issues have been defined in hospitalized patients with COVID-19, including inflammatory plaque rupture, cardiac stress due to high cardiac output, and thrombosis [168, 169] . Those with pre-existing conditions were shown to have an increased risk of heart failure [170] . Cardiovascular sequelae using cardiovascular magnetic resonance imaging in patients who recovered from recent infection with COVID-19

were investigated in 100 patients [170] . Of these patients, 78% had ongoing cardiac involvement and 60% had myocardial inflammation [170] . Evidence of vasculitis, the inflammation of blood vessels, has also been described [171] . Reports of palpitations and orthostatic intolerance have also been made, but these are limited to single case studies [172] . ME/CFS patients also have reported cardiovascular problems, including abnormal blood pressure, hypertension, and orthostatic intolerance [173] . It currently remains unclear whether these symptoms of autonomic dysfunction in COVID-19 patients are caused by direct viral invasion and tissue destruction or indirect effects of ARDS, including hypoxemia, inflammation, and/or thrombosis. It is possible that a combination of both mechanisms is involved.

The permanent and often uncurable vascular damage caused by the SARS strain was marked by thromboembolism, micro-infarctions, pulmonary embolism, and other dysfunctions [174] . Cardiovascular post-COVID-19 complications have been diagnosed in hospitalized patients and included inflammatory plaque rupture, cardiac stress, and stent thrombosis [170] .

Investigations into cardiovascular sequelae in 100 patients who have recovered from recent SARS-CoV-2 infection indicated that 78% of patients had ongoing cardiac complications and 60% had myocardial inflammation [170] . Another similar study also detected signs of vasculitis, the inflammation of blood vessels [171] . One other single case study reported palpitations and orthostatic intolerance [172] . The observed pathologies could be associated with virus-induced hypoxemia, inflammation, and/or thrombosis. In comparison to COVID-19, ME/CFS patients were also diagnosed with cardiovascular pathologies, abnormal blood pressure, hypertension, and orthostatic intolerance [173] .

A variety of GI manifestations have been reported in COVID-19 patients, including nausea, vomiting and abdominal pain. The second most common COVID-19 symptom is diarrhea, which was registered in up to 70% of patients [175] [176] [177] . COVID-19 patients presented with diarrhea had 2.7 times higher odds of having longer duration of symptoms [178] . Some patients have reported GI symptoms in the absence of respiratory symptoms [74] .

ACE2 receptors are highly expressed in the glandular cells of gastric, duodenal, and rectal epithelia. Direct viral invasion into GI tissue may contribute to the symptom onset [179] , consequently, causing nervous system dysregulation, including disruptions in the dorsal vagal complex (DVC). Vagal neurocircuits have important roles in regulating nausea and vomiting [180] , which were reported in COVID-19 patients [181] .

Changes in microbiome composition, including underrepresentation of key commensal bacterial colonies such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacterial, were associated with immunomodulation in COVID-19 patients [182] .

Microbiome changes, including SARS-CoV-2 invasion, often result in variations of cytokine and inflammatory marker levels [182] . A study investigating alterations in gut microbiota suggested that dysbiosis in COVID-19 patients persisted even after infection clearance [183] .

Changes in microbiome and GI-related symptoms have been reported in individual studies in ME/CFS patients [184] . It has been suggested that gut-located pathogens and/or infectionrelated toxins produced by invaded pathogens may translocate from the GI tract into other tissues and trigger ME/CFS symptoms [54] . A systematic review on enteric dysbiosis in ME/CFS, however, found that there was limited evidence of this condition being involved in the pathomechanism of ME/CFS [185] .

GI-associated pathologies were reported in post COVID-19 condition patients [186, 187] . Interaction between SARS-CoV-2 particles and host GI proteins, including Bromodomain-Containing Proteins 2 and 4 (BRD2 and BRD4) was detected [188] . Expression of BRD4, the protein involved in the innate immune reaction to SARS-CoV-2, has been previously observed in the small intestine [188] . Notably, the crosstalk between SARS-CoV-2-located protein E and BRD4 have been shown to activate macrophage senescence [188] .

Previous investigations suggested that BRD4 signalling may be associated with muscle weakness (a potential link to PEM, a major ME/CFS symptom) [189] . Importantly, there is limited information available on the pathomechanism of post COVID-19 condition in the GI system.

There is evidence of persistent physiological and psychological sequelae in COVID-19

survivors. The multi-system post-COVID-19 sequalae that have been observed include disruption in neurological, cardiovascular, and musculoskeletal pathways [129] . However, the diversity of the observed complications hinders the development of efficient treatments. Post COVID-19 condition may represent a number of different post-viral syndromes that require appropriate classification [190] . All long-term symptoms of post COVID-19 condition should be monitored and recorded. Large data collection and registration of symptoms is required to determine whether long-term symptoms are due to a post-viral syndrome such as ME/CFS. The process of data collection and analysis should be controlled for all confounding factors including consequences of intensive care hospitalization, social isolation, and diet-related effects (diet-linked anaemia). Timely collection of data and identification of physiological mechanisms underlying the long-term clinical manifestations of COVID-19 and post COVID-19 condition are vital for the relevant design of effective therapies. While available vaccinations are expected to reduce the devastating health effects of SARS-CoV-2, it is also predicted that SARS-CoV-2 mutations may turn the pandemic into an ongoing issue [191] .

COVID-19 and post COVID-19 condition follow-up studies have been initiated. Some of these studies are focused on damaged organ systems (e.g. respiratory and cardiovascular system organs), while others will monitor and record all adverse effects. For instance, the posthospitalisation COVID-19 study (PHOSP-COVID https://www.phosp.org/) intends to follow 10,000 patients for 1 year in the United Kingdom [192] . A similar study was initiated in the USA (go.nature.com/3mfqqxc). The British Heart Foundation also declared several new COVID-19-based research programmes. One of these projects will follow COVID-19 hospitalized patients for six months and all signs of damage will be recorded. In the European Union, the CAPACITY registry initiative is looking to collect follow-up reports about SARS-CoV-2 infected patients from dozens of European hospitals [193] . The studies aim to collect data from blood tests and scans, using virus-related biomarkers.

Several antiviral and anti-inflammatory agents (including remdesivir, dexamethasone), monoclonal antibodies and immunomodulatory substances (bamlanivimab, casirivimab, baricitinib, tocilizumab) were used as emergency treatment during the management of severe acute COVID-19 in risk factors [194, 195] . However, there is currently no validated treatment for post COVID-19 condition. Considering prospective interventions, Ca 2+ -regulating treatment can be explored as promising, given Ca 2+ signalling was shown to be modified in both post-COVID-19 and ME/CFS patients. The use of dihydropyridine Ca 2+ channel blockers, including nifedipine (TRPM3 agonist [196] ) and amlodipine, have been suggested as an effective therapeutic approach to reduce mortality in elderly COVID-19 patients [197] . The decreased serum Ca 2+ level may serve similar anti-viral purposes [150] . Accordingly, Cabanas et al have recently found that TRPM3 function in ME/CFS patients can be restored by in the presence of the mu (μ)-opioid receptor antagonist, naltrexone, which also indicated antiinflammatory properties [198, 199] . Recently, a pilot study was registered to test the effect of low-dose naltrexone in combination with nicotinamide adenine dinucleotide supplement for the treatment of post COVID-19 condition (Clinical trial #NCT04604704).

The use of ACE inhibitors was suggested as a potential therapeutic approach for prevention of post-COVID-19 complications, including organ injury [2, 200] . However, ACE inhibitors should be used cautiously as they were found to increase plasma angiotensin levels (pro-inflammatory effect) and cardiac ACE2 expression [201] . To minimize the potential complications, the ACE2-related pathway was also explored [200] . The ACE2-pathwaytargeting agent and Mas receptor activator BIO101 (20-hydroxyecdysone) is currently being tested (the trial started on September 1, 2020) for management of acute SARS-CoV-2 infection and related complications [200] . BIO101 activates the Mas-receptor and triggers antiinflammatory, anti-thrombotic, and anti-fibrotic effects, thus restoring internal homeostasis in COVID-19 patients [200] .

Nearly two years into the worldwide COVID-19 pandemic, post COVID-19 condition syndrome has proven to be a serious and lingering problem for many recovering patients. This 

Authors declare no conflict of interest. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Th1-Th2 responses CFS is dominated by Th1 cytokines network, consisting of cytokine nodes IL-1b, IL-4, IFN-γ and TNFα. However, the shift toward an allergic or Th2 pattern associated with autoimmunity was also observed in ME/CFS patients who also exhibited poorer sleep and high levels of basal salivary cortisol. Highly attenuated Th1 and Th17 immune responses were observed in ME/CFS. High Th2 marker expression but weak interaction patterns pointed to an established Th2 inflammatory milieu. Another study did not find any differences in the level of IL-17 between ME/CFS and control patients. [83, [215] [216] [217] [ 218] Decreased circulating eosinophil numbers in 50%-80% of the hospitalized patients. Eosinopenia (52.9%) was observed in most severe COVID-19 patients.

Inconclusive findings: Eosinophils count was not significantly different to controls, but eosinophil count was significantly associated with indices of autonomic nervous activity, plasma cortisol, and blood monocyte in ME/CFS group. increase in CCL11 (eotaxin), a chemokine involved in eosinophil recruitment was detected in ME/CFS. Innate and adaptive systems, monocytemacrophages of COVID-19 patients produced massive amounts of cytokines and chemokines, including IFNg, TNF, CCL4, CCL5, IL-1α and IL-1β, neutrophil chemoattractant chemokine IL-8 (CXCL8). IL-6 concentrations were significantly higher in COVID-19 non-survivors. Accordingly, Tocilizumab (TCZ), a monoclonal antibody against interleukin-6 (IL-6) appears to be an effective treatment option in COVID-19 patients with a risk of cytokine storms.

The increased levels of pro-inflammatory cytokines (IL-1, IL-4, IL-5, TNFα, IL-10, IFN-γ, IL-12, LTa,), CD4+/ CD25+ T cells, increased expression of FOXP3 and VPACR2, and activation of NF-κB were detected in ME/CFS patients. IL-4 median concentration was increased 3-fold in CFS. Increased IL-6, produced by EBV-infected B cells, together with depressed levels of IL-15 was suggested to interfere with LT-α and IL-12 activation of NK cells and the resulting decreased IFN-γ production. Another study also observed lower INFg production by CD4+ T cells from ME/CFS patients. A larger post-exercise increase in IL-10 and Toll-like receptor 4 (TLR4) gene transcripts in CFS was observed.

The following cytokines were decreased in ME/CFS: IL-8, IL-13, and IL-15.

[ 90, 95, 217, [228] [229] [230] [231] [ 66, 232] Significantly higher levels of D-dimer, C-Acute-phase The elevated level of high-sensitivity CRP (hsCRP) was [233, 234] reactive protein (CRP), and procalcitonin were associated with severe patients compared to non-severe patients. The levels of chloride and calcium in blood of COVID-19 patients were significantly lower than those of non-COVID-19 patients. The levels of lactate dehydrogenase (LDH) and potassium were significantly higher in COVID-19. However, another study found decreased levels of CRP in COVID-19 patients when we compared CRP levels among patients with endogenously elevated CRP.

reactants found in ME/CFS patients. Patients with ME/CFS had significantly elevated level of TGF-β. [126, [235] [236] [237] Oxidative stress and hypoxia were observed in COVID-19 patients with severe pneumonia. Proinflammatory cytokines IL-6 and IL-1β release is triggered by activation of the Nod-like receptor family, pyrin domaincontaining 3 (NLRP3) inflammasome pathway that is associated with oxidative burst in mitochondria. However, COVID-19 monocytes had a reduced ability to perform oxidative burst, although they produced TNF and IFN-γ in vitro. A significantly high number of COVID-19 monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. Dysfunctional mitochondria/oxidative phosphorylation was associated with aging and defective immunological response to viral infections and chronic inflammation.

Cell death/mitochon dria/ energy metabolism Low ATP production and mitochondrial dysfunction is a source of autoimmunity accompanied by necrotic cell death.

Mitochondrial dysfunctions, including decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are involved in the ME/CFS pathophysiology.

The gut and immune cell mitochondria are proposed to be two important effectors that influence the circadian rhythm in ME/CFS pathophysiology. ME/CFS CD8+ T cells had reduced mitochondrial membrane potential. Both CD4+ and CD8+ T cells from patients with ME/CFS had reduced glycolysis at rest, whereas CD8+ T cells also had reduced glycolysis following activation. [15, 90, 135, 136, 142, 238] [ 239, 240] Exogenous or endogenous GC excess leads to the increased susceptibility to viral infections. GC excess was suggested to impact on COVID-19 infection clinical outcome. However, in hospitalized COVID-19 patients, the use of dexamethasone (DEX) resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.

ME/CFS appears to be associated with a disturbed hypothalamus-pituitary-adrenal (HPA)-axis. GCs suppress Th1 cells and cellular immunity but may favour Th2 responses and humoral immunity. It was postulated that in ME/CFS patients a decreased Th1/Th2 balance may be the result of selective effects of GC on the IL-10/IL-12 regulatory circuit. With CD4+ T cells from ME/CFS patients (compared with cells from controls), a 10-to 20-fold lower DEX concentration was needed to achieve 50% inhibition of IL-4 production and proliferation, indicating an increased sensitivity to DEX in ME/CFS patients. [231, 241] First Author Biography:

Dr Sukocheva completed Ph.D. in Biophysics in 1997 (Uzbekistan 

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Transient Receptor Potential Channels and Metabolism

Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients

COVID-19: Urgent Reconsideration of Lung Edema as a Preventable Outcome: Inhibition of TRPV4 As a Promising and Feasible Approach

Mitochondrial dynamics and their impact on T cell function

Low serum calcium: a new, important indicator of COVID-19 patients from mild/moderate to severe/critical

Conflicts over calcium and the treatment of COVID-19

Cerebral Micro-Structural Changes in COVID-19 Patients -An MRI-based 3-month Follow-up Study

Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study

Vasculitis changes in COVID-19 survivors with persistent symptoms: an [(18)F]FDG-PET/CT study

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation

Into the looking glass: Post-viral syndrome post COVID-19

The extended autonomic system, dyshomeostasis, and COVID-19

Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors

COVID-19 symptoms over time: comparing long-haulers to ME/CFS, Fatigue: Biomedicine, Health & Behavior (2021)

Post-Acute COVID-19 Symptoms, a Potential Link with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A 6-Month Survey in a Mexican Cohort

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review

A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques

Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review

Intra brainstem connectivity is impaired in chronic fatigue syndrome

Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome

What is Long-COVID and How Should We Manage It?

Regulation of IL-6 in Immunity and Diseases

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)

COVID-19-associated vasculitis and vasculopathy

Autonomic dysfunction in 'long COVID': rationale, physiology and management strategies

Cardiovascular characteristics of chronic fatigue syndrome

Long-term sequelae following previous coronavirus epidemics

Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors

Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention, and Management

Covid-19 and the digestive system

COVID-19 Disease Outcomes: Does Gastrointestinal Burden Play a Role?

How is the digestive system affected by coronavirus disease?

The role of vagal neurocircuits in the regulation of nausea and vomiting

Gastrointestinal Manifestations of COVID-19: A Review of What We Know

Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19

Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization

Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome

A systematic review of enteric dysbiosis in chronic fatigue syndrome/myalgic encephalomyelitis

The kids are not alright: A preliminary report of Post-COVID syndrome in university students

Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms

Targeting inflammation and cytokine storm in COVID-19

Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival

A dynamic review of the evidence around ongoing covid-19 symptoms

SARS-CoV-2 evolution and vaccines: cause for concern?

Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort

CAPACITY-COVID: a European Registry to determine the role of cardiovascular disease in the COVID-19 pandemic

Stabilizing mast cells by commonly used drugs: a novel therapeutic target to relieve post-COVID syndrome?

Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics

Orofacial Antinociceptive Effect of Nifedipine in Rodents Is Mediated by TRPM3, TRPA1, and NMDA Processes

Nifedipine and Amlodipine Are Associated With Improved Mortality and Decreased Risk for Intubation and Mechanical Ventilation in Elderly Patients Hospitalized for COVID-19

Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment

Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Testing the efficacy and safety of BIO101, for the prevention of respiratory deterioration, in patients with COVID-19 pneumonia (COVA study): a structured summary of a study protocol for a randomised controlled trial

Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19

Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia

Naturally activated adaptive immunity in COVID-19 patients

Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell Responses

Cellular Immune Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections

T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis

CXCL4 promoted the production of CD4(+)CD25(+)FOXP3(+)treg cells in mouse sepsis model through regulating STAT5/FOXP3 pathway

Severe COVID-19 is associated with deep and sustained multifaceted cellular immunosuppression

Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)

Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative and nitrosative stress biomarkers

Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients

Acute Upper Limb Ischemia in a Patient with COVID-19 Pneumonia

Immune system changes during COVID-19 recovery play key role in determining disease severity

Plasma cytokines in women with chronic fatigue syndrome

Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS)

A formal analysis of cytokine networks in chronic fatigue syndrome

Longitudinal Change of Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies in Patients with Coronavirus Disease

Antibody to Epstein-Barr virus deoxyuridine triphosphate nucleotidohydrolase and deoxyribonucleotide polymerase in a chronic fatigue syndrome subset

Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome

BRD4 contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake

Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19

Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls

Epstein-Barr Virus Induced Gene-2 Upregulation Identifies a Particular Subtype of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

T cell immunobiology and cytokine storm of COVID-19

Interleukin-6 and severity of COVID-19 patients in Hefei, China

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review

Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome

LPSinduced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone

Differential Diagnosis of COVID-19: Importance of Measuring Blood Lymphocytes, Serum Electrolytes, and Olfactory and Taste Functions

Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls

Inflammatory proteins are altered in chronic fatigue syndrome-A systematic review and meta-analysis

Targeting the NLRP3 Inflammasome in Severe COVID-19

Age-related mitochondrial dysfunction as a key factor in COVID-19 disease

Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 'long-haulers'?

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations

Glucocorticoid excess and COVID-19 disease

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial

CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone

Her research aims are linked to determination of the expression and cytotoxic potential of natural killer T-cells and the role of T-cells in development of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Rebekah's current PhD project is about the assessing of disability measures in ME/CFS patients. Rebekah contributed various other projects and published reviews about neurological, mitochondrial, and sleep-rel ated changes in ME/CFS patients

MSci by Research (UK), PhD, is an early career research fellow at Prof

He successfully published 28 research manuscripts (scopus ; ORCID) and currently involved in several inflammation-related clinical and bio-medical investigations. Dr Beeraka is interested in identification and development of clinical biomarkers for chronic diseases including inflammation

During his post-doctoral research at Penn State Cancer Institute, Hershey, Pennsylvania, USA, he investigated key signaling cascades involved in regulation of melanoma carcinogenesis

Ph.D, is the acting director of Institute of Physiologically Active Compounds of

He is the Head of laboratory of Natural Products Institute of Physiologically Active Compounds

He is a well-known specialist in the field of medicinal and natural chemistry, biochemistry, neurobiology and oncology. His current research interests are focused on the field of neuroprotection and drug design, as well as development of new clinical testing methods

After graduating with honors from Ivanovo State University in 2007, she entered the postgraduate study at the IPAC RAS, specializing in bioorganic chemistry, and in 2012 received her Ph.D. She is a specialist in the field of biochemistry, neurobiology, cytology, oncology, and preclinical drug development. Margarita E. Neganova is the author of more than 70 publications

He is an expert in neuroscience and biomechanics of the nervous system. Professor Nikolenko authored and coauthored over 500 scientific publications

Prof Nikolenko established a new scientific direction in CNS neuro-morphology and medical biomechanics associated with adaptation of nervous system to new environment and tsressrelated conditions. He formulated background laws of spinal cord kinesiology. Prof Nikolenko made significant contributions to the field of nervous system regeneration

is an assistant professor at the department of Human anatomy at Sechenov University. He is the Clinical Morphology lab Head at Research Institute of Human Morphology and a practicing reconstructive surgeon at Russian National Scientific Center of Surgery. He grew up in New York, USA, but chose to finish medical school in Russia

Sinelnikov's research interests include reparative regeneration of tissues, microvascular aspects of tissue degeneration, lymphatic diseases, and stem cell therapy. Dr Sinelnikov's current research aim is focused on investigation of degenerative disorders of lymphatic tissue associated with various pro

Prof. Kamal's overall biochemical research output had culminated in more than 560 publications in internationally respected journals. His research was pivotal in supporting the development of the novel anti-Alzheimer's agents from the laboratory to the clinic via collaboration with Dr Nigel H. Greig (Chief of Laboratory of Neurosciences

Professor Staines was awarded the first four-year international Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) full Professorial Fellowship. Professor Staines is an outstanding independent clinical researcher in the field of ME/CFS. His research is successfully supported by competitive/philanthropic national and international funding bodies. Professor Staines has been successful in attaining over $12 million research support funding to explore the clinical presentation and pathophysiology of ME/CFS

Prof Marshall-Gradisnik relocated, along with her research team, to Griffith University (GU) and with Professor Staines established the National Centre for Neuroimmunology and Emerging Disease (NCNED). In 2018, she was appointed to the National Health and Medical Research ME/CFS Advisory Committee and in the following year

Professor Marshall-Gradisnik has sustained success as an independent researcher and has been supported by competitive/philanthropic national and international funding bodies for over ten years

The authors, including