Modifiable contributing factors to COVID-19: A comprehensive review.

The devastating complications of coronavirus disease 2019 (COVID-19) result from an individual's dysfunctional immune response following the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS-CoV-2 exploits the dysfunctional immune system to trigger a chain of events ultimately leading to COVID-19. The current study identifies eighty immune system dysfunction-enabling toxic stressors and behaviors (hereafter called modifiable contributing factors (CFs)) that also link directly to COVID-19. Each CF is assigned to one of the five categories in the CF taxonomy shown in Section 3.3.: Lifestyle (e.g., diet, substance abuse); Iatrogenic (e.g., drugs, surgery); Biotoxins (e.g., micro-organisms, mycotoxins); Occupational/Environmental (e.g., heavy metals, pesticides); Psychosocial/Socioeconomic (e.g., chronic stress, lower education). The current study shows how each modifiable factor contributes to decreased immune system capability, increased inflammation and coagulation, and increased neural damage and neurodegeneration. It is unclear how real progress can be made in combatting COVID-19 and other similar diseases caused by viral variants without addressing and eliminating these modifiable CFs.

The biology of symptom-based disorders - time to act.

Symptom-based disorders are conditions that are characterised mostly by somatic symptoms rather than objectively identifiable signs. They are very common, including pain and fatigue disorders, functional gastrointestinal and respiratory disorders, and others, and they cause far greater disability than diseases where signs are prominent. Such conditions may sometimes be triggered by infection, as in Post Covid Syndrome (Cabral-Marques et al., 2022; Baiocchi et al., 2022) or physical or psychological trauma. By employing passive immunoglobulin transfer experimental approaches, recent research in several 'unexplained' chronic pain conditions has demonstrated that pathogenic IgG autoantibodies can explain several of these conditions' core symptoms and are ubiquitous in patients with severe phenotypes. The promise from placing positive resources into exploring the role of 'invisible', functional, non-inflammatory autoantibodies in symptom-based disorders across additional areas of Medicine includes patient empowerment and the development of new diagnostic tests and therapies.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown etiology, sharing a similar clinical presentation with the increasingly recognized post-COVID syndrome. We performed the first cross-sectional study of ME/CFS in a community population in Russia. Then we described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders. Of the cohort of 76 individuals who suggested themselves as suffering from ME/CFS, 56 were diagnosed with ME/CFS by clinicians according to ≥1 of the four most commonly used case definitions. Of the cohort of 14 individuals with post-COVID-19 syndrome, 14 met the diagnostic criteria for ME/CFS. The severity of anxiety/depressive symptoms did not correlate with the severity of fatigue either in ME/CFS or in post-COVID ME/CFS. Still, a positive correlation was found between the severity of fatigue and 20 other symptoms of ME/CFS related to the domains of "post-exertional exhaustion", "immune dysfunction", "sleep disturbances", "dysfunction of the autonomic nervous system", "neurological sensory/motor disorders" and "pain syndromes". Immunological abnormalities were identified in 12/12 patients with ME/CFS according to the results of laboratory testing. The prevalence of postural orthostatic tachycardia assessed in the active orthostatic test amounted to 37.5% in ME/CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02). There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group. Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls. The identified laser doppler flowmetry pattern corresponded to the hyperemic form of microcirculation disorders usually observed in acute inflammatory response or in case of systemic vasoconstriction failure.

Autoimmunity, COVID-19 Omicron Variant, and Olfactory Dysfunction: A Literature Review.

Smelling is a critical sense utilized daily. Consequently, smelling impairment or anosmia may lead to a reduction in life quality. Systemic diseases and particular autoimmune conditions can impair olfactory function; among others are Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis. Interactions between the olfactory process and the immune systems cause this phenomenon. Alongside autoimmune conditions, in the recent COVID-19 pandemic, anosmia was also described as a prevalent infection symptom. Nevertheless, the occurrence of anosmia is significantly less common in Omicron-infected patients. Several theories have been proposed to explain this phenomenon. One possibility is that the Omicron variant preferentially enters host cells via endocytosis, rather than plasma cell membrane fusion. This endosomal pathway is less dependent on the activation of Transmembrane serine protease 2 (TMPRSS2), expressed at the olfactory epithelium. As a result, the Omicron variant may have reduced efficiency in penetrating the olfactory epithelium, leading to a lower prevalence of anosmia. Furthermore, olfactory changes are known to be associated with inflammatory conditions. The Omicron variant elicits a less robust autoimmune and inflammatory response, believed to reduce the probability of anosmia. This review elaborates on the commonalities and differences in autoimmune and COVID-19 omicron-associated anosmia.

Dysregulated Levels of Circulating Autoantibodies against Neuronal and Nervous System Autoantigens in COVID-19 Patients.

BACKGROUND: COVID-19 is a heterogenous disease resulting in long-term sequela in predisposed individuals. It is not uncommon that recovering patients endure non-respiratory ill-defined manifestations, including anosmia, and neurological and cognitive deficit persisting beyond recovery-a constellation of conditions that are grouped under the umbrella of long-term COVID-19 syndrome. Association between COVID-19 and autoimmune responses in predisposed individuals was shown in several studies. AIM AND METHODS: To investigate autoimmune responses against neuronal and CNS autoantigens in SARS-CoV-2-infected patients, we performed a cross-sectional study with 246 participants, including 169 COVID-19 patients and 77 controls. Levels of antibodies against the acetylcholine receptor, glutamate receptor, amyloid ß peptide, alpha-synucleins, dopamine 1 receptor, dopamine 2 receptor, tau protein, GAD-65, N-methyl D-aspartate (NMDA) receptor, BDNF, cerebellar, ganglioside, myelin basic protein, myelin oligodendrocyte glycoprotein, S100-B, glial fibrillary acidic protein, and enteric nerve were measured using an Enzyme-Linked Immunosorbent Assay (ELISA). Circulating levels of autoantibodies were compared between healthy controls and COVID-19 patients and then classified by disease severity (mild [n = 74], severe [n = 65], and requiring supplemental oxygen [n = 32]). RESULTS: COVID-19 patients were found to have dysregulated autoantibody levels correlating with the disease severity, e.g., IgG to dopamine 1 receptor, NMDA receptors, brain-derived neurotrophic factor, and myelin oligodendrocyte glycoprotein. Elevated levels of IgA autoantibodies against amyloid ß peptide, acetylcholine receptor, dopamine 2 receptor, myelin basic protein, and α-synuclein were detected in COVID-19 patients compared with healthy controls. Lower IgA autoantibody levels against NMDA receptors, and IgG autoantibodies against glutamic acid decarboxylase 65, amyloid ß peptide, tau protein, enteric nerve, and S100-B were detected in COVID-19 patients versus healthy controls. Some of these antibodies have known clinical correlations with symptoms commonly reported in the long COVID-19 syndrome. CONCLUSIONS: Overall, our study shows a widespread dysregulation in the titer of various autoantibodies against neuronal and CNS-related autoantigens in convalescent COVID-19 patients. Further research is needed to provide insight into the association between these neuronal autoantibodies and the enigmatic neurological and psychological symptoms reported in COVID-19 patients.

Assessment of Hearing and Vestibular Functions in a Post-COVID-19 Patient: A Clinical Case Study.

SARS-CoV-2 infection may cause such complications as post-COVID-19 syndrome, which includes chronic fatigue, myalgia, arthralgia, as well as a variety of neurological manifestations, e.g., neuropathy of small fibers, hearing and vestibular dysfunction, and cognitive impairment. This clinical case describes a 41-year-old patient suffering from post-COVID-19 syndrome and chronic fatigue syndrome. A detailed examination was performed, including an in-depth study of peripheral and central hearing and vestibular functions, as well as small nerve fibers length and density in the skin and cornea of the eye. Contrary to expectations, no peripheral nervous system dysfunction was detected, despite the presence of dizziness and gait instability in the patient. Hearing tests (gap detection test and dichotic test) showed central auditory processing disorders. The evaluated lesion in the processing of temporal and verbal auditory information can be a significant factor contributing to additional overload of the neural activity and leading to chronic fatigue when performing daily activities in patients with CFS and post-COVID-19 complications.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in 2023.

In 2011, a syndrome entitled ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants; Shoenfeld's syndrome) was first described. ASIA aimed to organize under a single umbrella, the existing evidence regarding certain environmental factors which possess immune stimulatory properties, in order to shed light on a common pathway of autoimmune pathogenesis. Such environmental immune stimulators, or adjuvants, include among others: aluminum salts as in vaccines, various medical implants, as well as various infectious agents. After the launch of the ASIA syndrome, the expansion and recognition of this syndrome by different researchers from different countries began. During the past decades, evidence had been accumulating that (auto)immune symptoms can be triggered by exposure to environmental immune stimulatory factors that act as an adjuvant in genetically susceptible individuals. A panoply of unexplained subjective and autonomic-related symptoms has been reported in patients with ASIA syndrome. The current review summarizes and updates accumulated knowledge from the past decades, describing new adjuvants- (e.g. polypropylene meshes) and vaccine- (e.g. HPV and COVID vaccines) induced ASIA. Furthermore, a direct association between inflammatory/autoimmune diseases with ASIA syndrome, will be discussed. Recent cases will strengthen some of the criteria depicted in ASIA syndrome such as clear improvement of symptoms by the removal of adjuvants (e.g. silicone breast implants) from the body of patients. Finally, we will introduce additional factors to be included in the criteria for ASIA syndrome such as: (1) dysregulated non-classical autoantibodies directed against G-protein coupled receptors (GPCRs) of the autonomic nervous system and (2)) small fiber neuropathy (SFN), both of which might explain, at least in part, the development of 'dysautonomia' reported in many ASIA patients.

Cross-sectional analysis reveals autoantibody signatures associated with COVID-19 severity.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a broad spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients in a cohort of 231 individuals, of which 161 were COVID-19 patients (72 with mild, 61 moderate, and 28 with severe disease) and 70 were healthy controls. Dysregulated IgG and IgA autoantibody signatures, characterized mainly by elevated concentrations, occurred predominantly in patients with moderate or severe COVID-19 infection. Autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations while stratifying COVID-19 severity as indicated by random forest and principal component analyses. Furthermore, while young versus elderly COVID-19 patients showed only slight differences in autoantibody levels, elderly patients with severe disease presented higher IgG autoantibody concentrations than young individuals with severe COVID-19. This work maps the intersection of COVID-19 and autoimmunity by demonstrating the dysregulation of multiple autoantibodies triggered during SARS-CoV-2 infection. Thus, this cross-sectional study suggests that SARS-CoV-2 infection induces autoantibody signatures associated with COVID-19 severity and several autoantibodies that can be used as biomarkers of COVID-19 severity, indicating autoantibodies as potential therapeutical targets for these patients.

Editorial for "Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form".

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first reported in December 2019, has infected numerous subjects worldwide [...].

Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19.

In patients with severe #COVID19, increased levels of autoantibodies against PAR1 were found. These might serve as allosteric agonists of PAR1 on endothelial cells and platelets, and thus might contribute to the pathogenesis of microthrombosis in COVID-19. https://bit.ly/3pqM9Vv.

Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity.

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR). In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups. We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients. Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.

Shared 6mer Peptides of Human and Omicron (21K and 21L) at SARS-CoV-2 Mutation Sites.

We investigated the short sequences involving Omicron 21K and Omicron 21L variants to reveal any possible molecular mimicry-associated autoimmunity risks and changes in those. We first identified common 6mers of the viral and human protein sequences present for both the mutant (Omicron) and nonmutant (SARS-CoV-2) versions of the same viral sequence and then predicted the binding affinities of those sequences to the HLA supertype representatives. We evaluated change in the potential autoimmunity risk, through comparative assessment of the nonmutant and mutant viral sequences and their similar human peptides with common 6mers and affinities to the same HLA allele. This change is the lost and the new, or de novo, autoimmunity risk, associated with the mutations in the Omicron 21K and Omicron 21L variants. Accordingly, e.g., the affinity of virus-similar sequences of the Ig heavy chain junction regions shifted from the HLA-B*15:01 to the HLA-A*01:01 allele at the mutant sequences. Additionally, peptides of different human proteins sharing 6mers with SARS-CoV-2 proteins at the mutation sites of interest and with affinities to the HLA-B*07:02 allele, such as the respective SARS-CoV-2 sequences, were lost. Among all, any possible molecular mimicry-associated novel risk appeared to be prominent in HLA-A*24:02 and HLA-B*27:05 serotypes upon infection with Omicron 21L. Associated disease, pathway, and tissue expression data supported possible new risks for the HLA-B*27:05 and HLA-A*01:01 serotypes, while the risks for the HLA-B*07:02 serotypes could have been lost or diminished, and those for the HLA-A*03:01 serotypes could have been retained, for the individuals infected with Omicron variants under study. These are likely to affect the complications related to cross-reactions influencing the relevant HLA serotypes upon infection with Omicron 21K and Omicron 21L.

The intercorrelations between blood levels of ferritin, sCD163, and IL-18 in COVID-19 patients and their association to prognosis.

Coronavirus disease 2019 (COVID-19) is associated with immune dysregulation, severe respiratory failure, and multiple organ dysfunction caused by a cytokine storm involving high blood levels of ferritin and IL-18. Furthermore, there is a resemblance between COVID-19 and macrophage activation syndrome (MAS) characterized by high concentrations of soluble CD163 (sCD163) receptor and IL-18. High levels of ferritin, IL-18, and sCD163 receptor are associated with "hyperferritinemic syndrome", a family of diseases that appears to include COVID-19. In this retrospective cohort study, we tested the association and intercorrelations in the serum levels of ferritin, sCD163, and IL-18 and their impact on the prognosis of COVID-19. We analyzed data of 70 hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The levels of sCD163, ferritin, and IL-18 were measured and the correlation of these parameters with the respiratory deterioration and overall 30-day survival was assessed. Among the 70 patients, 60 survived 30 days from hospitalization. There were substantial differences between the subjects who were alive following 30 days compared to those who expired. The differences were referring to lymphocyte and leukocyte count, CRP, D-dimer, ferritin, sCD163, and IL-18. Results showed high levels of IL-18 (median, 444 pg/mL in the survival group compared with 916 pg/mL in the mortality group, p-value 8.54 × 10-2), a statistically significant rise in levels of ferritin (median, 484 ng/mL in the survival group compared with 1004 ng/mL in the mortality group p-value, 7.94 × 10-3), and an elevated value of in sCD163 (mean, 559 ng/mL in the survival group compared with 840 ng/mL in the mortality group, p-value 1.68 × 10-2). There was no significant correlation between the rise of ferritin and the levels sCD163 or IL-18. Taken together, sCD163, ferritin, and IL-18 were found to correlate with the severity of COVID-19 infection. Although these markers are associated with COVID-19 and might contribute to the cytokine storm, no intercorrelation was found among them. It cannot be excluded though that the results depend on the timing of sampling, assuming that they play distinct roles in different stages of the disease course. The data represented herein may provide clinical benefit in improving our understanding of the pathological course of the disease. Furthermore, measuring these biomarkers during the disease progression may help target them at the right time and refine the decision-making regarding the requirement for hospitalization.

Autoimmune Autonomic Dysfunction Syndromes: Potential Involvement and Pathophysiology Related to Complex Regional Pain Syndrome, Fibromyalgia, Chronic Fatigue Syndrome, Silicone Breast Implant-Related Symptoms and Post-COVID Syndrome.

The pathophysiological mechanisms involved in chronic disorders such as complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant-related symptoms, and post-COVID syndrome have not been clearly defined. The course of the pain in some of the syndromes, the absence of evident tissue damage, and the predominance of alterations in the autonomic nervous system are shared similarities between them. The production of autoantibodies following a trigger in the syndromes was previously described, for instance, trauma in complex regional pain syndrome, infectious agents in fibromyalgia, chronic fatigue syndrome, and post-COVID syndrome, and the immune stimulation by silicone in women with breast implants. In fact, the autoantibodies produced were shown to be directed against the autonomic nervous system receptors, leading to the amplification of the perception of pain alongside various clinical symptoms seen during the clinical course of the syndromes. Therefore, we viewed autoantibodies targeting the autonomic nervous system resulting in autonomic dysfunction as likely the most comprehensive explanation of the pathophysiology of the disorders mentioned. Based on this, we aimed to introduce a new concept uniting complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant-related symptoms, and post-COVID syndrome, namely "autoimmune autonomic dysfunction syndromes". Due to its etiological, pathophysiological, and clinical implications, the suggested term would be more precise in classifying the syndromes under one title. The new title would doubtlessly facilitate both laboratory and clinical studies aimed to improve diagnosis and make treatment options more directed and precise.

The mosaic of autoimmunity - Finally discussing in person. The 13th international congress on autoimmunity 2022 (AUTO13) Athens.

While autoimmunity is a branch of medicine linked to every single organ system via direct and indirect pathways, meeting in person to discuss autoimmunity during the 13th international congress on autoimmunity (AUTO13) with participants from all over the world had a very good reason. The mechanisms involved in autoimmune diseases are of extreme importance and in fact critical in understanding the course of diseases as well as selecting proper therapies. COVID-19 has served as a great example of how autoimmunity is deeply involved in the disease and directly correlated to severity, morbidity, and mortality. For instance, initially the term cytokine storm dominated, then COVID-19 was addressed as the new member of the hyperferritinemic syndrome, and also the use of immunosuppressants in patients with COVID-19 throughout the pandemic, all shed light on the fundamental role of autoimmunity. Unsurprisingly, SARS-CoV-2 was called the "autoimmune virus" during AUTO13. Subsequently, the correlation between autoimmunity and COVID-19 vaccines and post-COVID, all were discussed from different autoimmune aspects during the congress. In addition, updates on the mechanisms of diseases, autoantibodies, novel diagnostics and therapies in regard to autoimmune diseases such as antiphospholipid syndrome, systemic lupus erythematosus, systemic sclerosis and others, were discussed in dedicated sessions. Due to the magnificence of the topics discussed, we aimed to bring in our article hereby, the pearls of AUTO13 in terms of updates, new aspects of autoimmunity, and interesting findings. While more than 500 abstract were presented, concluding all the topics was not in reach, hence major findings were summarized.

The Role of Exposomes in the Pathophysiology of Autoimmune Diseases II: Pathogens.

In our continuing examination of the role of exposomes in autoimmune disease, we use this review to focus on pathogens. Infections are major contributors to the pathophysiology of autoimmune diseases through various mechanisms, foremost being molecular mimicry, when the structural similarity between the pathogen and a human tissue antigen leads to autoimmune reactivity and even autoimmune disease. The three best examples of this are oral pathogens, SARS-CoV-2, and the herpesviruses. Oral pathogens reach the gut, disturb the microbiota, increase gut permeability, cause local inflammation, and generate autoantigens, leading to systemic inflammation, multiple autoimmune reactivities, and systemic autoimmunity. The COVID-19 pandemic put the spotlight on SARS-CoV-2, which has been called "the autoimmune virus." We explore in detail the evidence supporting this. We also describe how viruses, in particular herpesviruses, have a role in the induction of many different autoimmune diseases, detailing the various mechanisms involved. Lastly, we discuss the microbiome and the beneficial microbiota that populate it. We look at the role of the gut microbiome in autoimmune disorders, because of its role in regulating the immune system. Dysbiosis of the microbiota in the gut microbiome can lead to multiple autoimmune disorders. We conclude that understanding the precise roles and relationships shared by all these factors that comprise the exposome and identifying early events and root causes of these disorders can help us to develop more targeted therapeutic protocols for the management of this worldwide epidemic of autoimmunity.

Autoantibodies and SARS-CoV2 infection: The spectrum from association to clinical implication: Report of the 15th Dresden Symposium on Autoantibodies.

The relation between infections and autoimmune diseases has been extensively investigated. Multiple studies suggest a causal relation between these two entities with molecular mimicry, hyperstimulation and dysregulation of the immune system as plausible mechanisms. The recent pandemic with a new virus, i.e., SARS-CoV-2, has resulted in numerous studies addressing the potential of this virus to induce autoimmunity and, eventually, autoimmune disease. In addition, it has also revealed that pre-existing auto-immunity (auto-Abs neutralizing type I IFNs) could cause life-threatening disease. Therefore, the topic of the 15th Dresden Symposium on Autoantibodies was focused on autoimmunity in the SARS-CoV-2 era. This report is a collection and distillation of the topics presented at this meeting.