Long COVID and the cardiovascular system—elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: a joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases

Cardiovascular Research, Journal Year: 2022, Volume and Issue: 119(2), P. 336 - 356

Published: July 25, 2022

Abstract Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available cardiovascular manifestations of long COVID. In addition chronic fatigue, which is common symptom COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, newly developed supraventricular ventricular arrhythmias. Imaging heart vessels provided evidence chronic, post-infectious perimyocarditis consequent left right failure, arterial wall inflammation, microthrombosis in certain patient populations. Better understanding underlying cellular molecular mechanisms will aid development effective treatment strategies its manifestations. A number have been proposed, including those involving direct effects on myocardium, microthrombotic damage endothelium, persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation, inflammatory markers, are not highly predictive either presence outcome when measured 3 infection. Further studies needed understand mechanisms, identify specific guide future preventive treatments address sequelae.

Language: Английский

---

Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 816 - 816

Published: March 6, 2023

The development of long-term symptoms coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed "long COVID" or post-acute sequela COVID-19 (PASC), can implicate persistent neurological complications in up to one third patients and present as fatigue, "brain fog", headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, peripheral neuropathy. Pathogenic mechanisms these long COVID remain largely unclear; however, several hypotheses both nervous system systemic pathogenic such SARS-CoV2 viral persistence neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, endotheliopathy. Outside the CNS, SARS-CoV-2 invade support stem cells olfactory epithelium leading alterations function. infection may induce abnormalities innate adaptive immunity including monocyte expansion, T-cell exhaustion, prolonged cytokine release, which cause neuroinflammatory responses microglia activation, white matter abnormalities, microvascular changes. Additionally, clot formation occlude capillaries endotheliopathy, due protease activity complement contribute hypoxic neuronal injury blood-brain barrier dysfunction, respectively. Current therapeutics target pathological by employing antivirals, decreasing inflammation, promoting regeneration. Thus, from laboratory evidence clinical trials literature, we sought synthesize pathophysiological pathways underlying potential therapeutics.

Language: Английский

---

Dysregulated naive B cells and de novo autoreactivity in severe COVID-19

Nature, Journal Year: 2022, Volume and Issue: 611(7934), P. 139 - 147

Published: Aug. 31, 2022

Abstract Severe SARS-CoV-2 infection 1 has been associated with highly inflammatory immune activation since the earliest days of COVID-19 pandemic 2–5 . More recently, these responses have emergence self-reactive antibodies pathologic potential 6–10 , although their origins and resolution remained unclear 11 Previously, we others identified extrafollicular B cell activation, a pathway formation new autoreactive in chronic autoimmunity 12,13 as dominant feature severe critical (refs. 14–18 ). Here, using single-cell repertoire analysis patients mild disease, identify expansion naive-derived, low-mutation IgG1 population antibody-secreting cells (ASCs) reflecting features low selective pressure. These correlate progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens carbamylated proteins, emerging 10–15 after onset symptoms. Detailed low-selection compartment shows high frequency clonotypes specific for both autoantigens, including pathogenic autoantibodies glomerular basement membrane. We further contraction this on recovery, re-establishment tolerance standards concomitant loss acute-derived ASCs irrespective antigen specificity. However, serological autoreactivity persists subset postacute sequelae, raising important questions to contribution continuing symptomology recovery. In summary, study demonstrates origins, breadth COVID-19, implications early intervention treatment post-COVID sequelae.

Language: Английский

---

Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system

Cardiovascular Diabetology, Journal Year: 2022, Volume and Issue: 21(1)

Published: Sept. 21, 2022

Post-acute sequelae of COVID-19 (PASC), also now known as long COVID, has become a major global health and economic burden. Previously, we provided evidence that there is significant insoluble fibrin amyloid microclot load in the circulation individuals with these microclots entrap substantial number inflammatory molecules, including those might prevent clot breakdown. Scientifically, most challenging aspect this debilitating condition traditional pathology tests such serum CRP (C-reactive protein) may not show any abnormal markers, albeit measure only soluble molecules. Elevated, or biomarkers IL-6, D-Dimer fibrinogen indicate an increased risk for thrombosis host immune response COVID-19. The absence standard tests, result amount confusion patients clinicians, are extremely sick even bed-ridden but no regular identifiable reason their disease. Biomarkers currently available cannot detect molecules present identified therefore unable to confirm presence mechanisms drive formation.

Language: Английский

---

Autoantibodies targeting GPCRs and RAS-related molecules associate with COVID-19 severity

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: March 9, 2022

Abstract COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand role these immune globulins in pathogenesis disease, it is important explore spectra. Here we show, by a cross-sectional study 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate clinical severity COVID-19. Patients moderate severe disease are characterized higher levels than healthy controls those mild disease. Among anti-GPCR autoantibodies, machine learning classification identifies chemokine receptor CXCR3 molecule AGTR1 as targets for antibodies strongest association severity. Besides antibody levels, network signatures also changing patients intermediate or high Although our current previous studies identify natural components human biology, their deregulated level pattern alterations might predict

Language: Английский

---

The intersection of COVID-19 and autoimmunity

Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 131(24)

Published: Oct. 28, 2021

Acute COVID-19, caused by SARS-CoV-2, is characterized diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute pathogenesis of severe COVID-19. Researchers working at intersection COVID-19 autoimmunity recently gathered an American Autoimmune Related Diseases Association Noel R. Rose Colloquium address current state knowledge regarding two important questions: Does established predispose COVID-19? And, same time, can SARS-CoV-2 trigger de novo autoimmunity? Indeed, work date demonstrated 10% 15% patients critical pneumonia exhibit autoantibodies against type I interferons, suggesting preexisting underlies disease in some patients. Other studies have identified functional following such as those promote thrombosis or antagonize cytokine signaling. These may arise a predominantly extrafollicular B cell response more prone generating autoantibody-secreting cells. This Review highlights understanding, evolving concepts, unanswered questions provided this unique opportunity determine mechanisms which viral be exacerbated by, even trigger, autoimmunity. The potential role post-acute sequelae also discussed.

Language: Английский

---

From rare disorders of immunity to common determinants of infection: Following the mechanistic thread

Cell, Journal Year: 2022, Volume and Issue: 185(17), P. 3086 - 3103

Published: Aug. 1, 2022

The immense interindividual clinical variability during any infection is a long-standing enigma. Inborn errors of IFN-γ and IFN-α/β immunity underlying rare infections with weakly virulent mycobacteria seasonal influenza virus have inspired studies two common infections: tuberculosis COVID-19. A TYK2 genotype impairing production accounts for about 1% cases, autoantibodies neutralizing account 15% critical COVID-19 cases. discovery inborn mechanisms drove the identification monogenic or autoimmune determinants related infections. This “rare-to-common” genetic mechanistic approach to infectious diseases may be heuristic value.

Language: Английский

---

Human autoantibodies underlying infectious diseases

The Journal of Experimental Medicine, Journal Year: 2022, Volume and Issue: 219(4)

Published: March 23, 2022

The vast interindividual clinical variability observed in any microbial infection—ranging from silent infection to lethal disease—is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of corresponding cytokine or response pathway. against type I IFNs COVID-19 pneumonia adverse reactions live attenuated yellow fever virus vaccine. II IFN severe disease caused environmental tuberculous mycobacteria, other intra-macrophagic microbes. IL-17A/F IL-6 are less common mucocutaneous candidiasis staphylococcal diseases, respectively. Inborn autoantibodies GM-CSF pulmonary alveolar proteinosis; associated infections well characterized. In individual patients, preexist with pathogen concerned disease. Human antibody-driven autoimmunity can interfere that essential for protective immunity agents but otherwise redundant, thereby underlying diseases.

Language: Английский

---

Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 7, 2022

Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) neurological symptoms. Some clinical attributes of MIS-C—such as persistent fever, rashes, conjunctivitis oral mucosa changes (red fissured lips strawberry tongue)—overlap with features Kawasaki (KD). In addition, shares striking similarities toxic shock (TSS), which triggered by bacterial superantigens (SAgs). The remarkable between TSS prompted search for SAg-like structures the virus discovery unique motif highly similar to Staphylococcal enterotoxin B (SEB) fragment spike 1 (S1) glycoprotein. Computational studies suggest has high affinity binding T-cell receptors (TCRs) MHC Class II proteins. Immunosequencing peripheral blood samples from patients revealed profound expansion TCR β variable gene 11-2 (TRBV11-2), correlates severity serum cytokine levels, consistent SAg-triggered immune response. sequence analysis further identified conserved neurotoxin-like motifs alter neuronal cell function contribute symptoms COVID-19 patients. Additionally, autoantibodies are detected during MIS-C, indicate development post-SARS-CoV-2 autoreactive autoimmune responses. Finally, prolonged persistence RNA gut, increased gut permeability elevated levels circulating S1 have been observed MIS-C. Accordingly, we hypothesize continuous exposure viral promote autoimmunity leading post-acute syndromes, long COVID, well complications resulting infection.

Language: Английский

---

COVID-19, post-acute COVID-19 syndrome (PACS, “long COVID”) and post-COVID-19 vaccination syndrome (PCVS, “post-COVIDvac-syndrome”): Similarities and differences

Pathology - Research and Practice, Journal Year: 2023, Volume and Issue: 246, P. 154497 - 154497

Published: May 3, 2023

Worldwide there have been over 760 million confirmed coronavirus disease 2019 (COVID-19) cases, and 13 billion COVID-19 vaccine doses administered as of April 2023, according to the World Health Organization. An infection with severe acute respiratory syndrome 2 (SARS-CoV-2) can lead an disease, i.e. COVID-19, but also a post-acute (PACS, "long COVID"). Currently, side effects vaccines are increasingly being noted studied. Here, we summarise currently available indications discuss our conclusions that (i) these specific similarities differences PACS, (ii) new term should be used refer (post-COVID-19 vaccination syndrome, PCVS, colloquially "post-COVIDvac-syndrome"), (iii) is need distinguish between (ACVS) (PACVS) - in analogy PACS ("long Moreover, address mixed forms caused by natural SARS-CoV-2 vaccination. We explain why it important for medical diagnosis, care research use terms (PCVS, ACVS PACVS) order avoid confusion misinterpretation underlying causes enable optimal therapy. do not recommend "Post-Vac-Syndrome" imprecise. The article serves current problem "medical gaslighting" relation PCVS raising awareness among professionals supplying appropriate terminology disease.

Language: Английский

---