Autoři uvádějí přehled forem celkové zánětlivé reakce vyvolané syndromem uvolnění cytokinů a tzv. cytokinovou bouří. Mezi spouštěče nekontrolovaného uvolnění cytokinů řadíme infekce, systémová onemocnění, rozsáhlé chirurgické výkony, imunoterapii nádorů ianafylaxi. Nadměrná proliferace aktivovaných T-lymfocytů a makrofágů vyvolává cytokinovou bouři také u hemofagocytující lymfohistiocytózy a syndromu aktivovaných makrofágů. Tyto stavy se společnými klinickými znaky vyvolané systémovým zánětem vedou k hemodynamické nestabilitě a až k multiorgánovému selhání. V roce 2020 byla nejčastěji uváděným termínem spojeným s onemocněním COVID-19 cytokinová bouře. Mezi rizikové faktory jejího vzniku patří genetická predispozice, vyšší věk, obezita nad 30 BMI, kardiovaskulární onemocnění, chronická obstrukční plicní nemoc, chronické onemocnění ledvin, nádorová onemocnění. U dětí se za 2–6 týdnů po expozici SARS-CoV-2 může rozvinout systémový zánět postihující především kardiovaskulární aparát. Diferenciální diagnostika těchto klinických obrazů vyvolaných cytokinovou bouří bývá na počátku obtížná, i když patofyziologické mechanismy postižení jsou si podobné. Možností ovlivnění rozvoje cytokinové bouře je podání monoklonálních protilátek
The authors present an overview of the form of the overall inflammatory response– cytokine release syndrome and cytokine storm syndrome. Triggers starting the reaction are infection, systemic diseases, extensive surgical procedures, tumor immunotherapy and rarely anaphylaxis. Excessive proliferation of activated T-lymphocytes and macrophages causes acytokine storm in hemophagocytic lymphohistiocytosis and activated macrophage syndrome. These conditions with common clinical features induced by systemic inflammation lead to hemodynamic instability and even multiorgan failure. In 2020, at the same time as the onset of the COVID-19 pandemic, the most common term associated with disease complications was acytokine storm. Risk factors include genetic predisposition but in patients with COVID-19 already proven age, obesity above 30 BMI, cardiovascular disease, type 2 diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, cancer. Children may develop systemic inflammation, mainly affecting the cardiovascular system, 2–6weeks after SARS-CoV-2 exposure. Differential diagnostic of these conditions is often difficult at first, although the patho-physiological mechanisms are similar. The possibility of influencing the development of the systemic reaction and the severity of the cytokine storm is the treatment with monoclonal antibodies
Syndrom uvolnění cytokinů, cytokine release syndrom, je systémová zánětlivá odpověď organismu vyvolaná vystupňovanou aktivací imunitního systému v reakci na různé faktory. Vysoká incidence cytokine release syndromu je zejména po imunoterapii T-buňkami chimérického receptoru antigenu, která je vysoce efektivní na refrakterní nebo opakovaně relabující hematologické malignity z B-buněk. Syndrom uvolnění cytokinů vzniká v důsledku nepřiměřené imunitní aktivace lymfocytů, makrofágů nebo myeloidních buněk s následným masivním uvolněním zánětlivých cytokinů. V případě terapie T-buňkami chimérického receptoru antigenu se příznaky objevují v řádu dnů po infuzi, což koreluje s maximem in vivo expanze T-lymfocytů. Klíčovou roli v patofyziologii hraje monocyto-makrofágový systém, který je hlavním zdrojem nejdůležitějších cytokinů. Hlavním mediátorem toxicity je interleukin 6. Ke klinickému průběhu patří horečka, hypotenze a hypoxie, těžké formy jsou klinicky neodlišitelné od sepse a můžou vést k multiorgánovému selhání. Vzhledem k tomu, že je imunoterapie T-buňkami chimérického receptoru antigenu potenciálně kurativní, měla by být pacientům po jejím podání poskytována plná resuscitační péče. V případě těžkého syndromu z uvolnění cytokinů je indikována léčba tocilizumabem, po jehož podání obvykle symptomy rychle odezní. Výzvou v klinické praxi bývá odlišení cytokine release syndromu od jiných závažných stavů, které mohou probíhat i konkomitantně a mohou vyžadovat odlišný terapeutický přístup.
Cytokine release syndrome is an acute systemic inflammatory response triggered by overactivation of the immune system that may be initiated by a variety of factors. The incidence of cytokine release syndrome is high, especially after immunotherapy with chimeric antigen receptor T-cells, which is effective for refractory or recurrent B cell hematological malignancies. Cytokine release syndrome occurs due to a high level of immune activation of lymphocytes, macrophages, or myeloid cells with a subsequent massive release of inflammatory cytokines. After chimeric antigen receptor T-cell therapy, symptoms appear within days of infusion, which correlates with the maximum T-cells expansion. The monocyte-macrophage system, which is the main source of the most important cytokines, plays a key role in pathophysiology. The central mediator of toxicity is interleukin 6. Cytokine release syndrome is presented by fever, hypotension, and hypoxia, severe forms are clinically indistinguishable from sepsis and may lead to multiorgan failure. Because chimeric antigen receptor T-cell immunotherapy is a potentially curative treatment, patients should be provided with full resuscitation care after administration of this therapy. In severe cytokine release syndrome, treatment with tocilizumab is indicated, after which symptoms usually resolve rapidly. The challenge in clinical practice is to differentiate cytokine release syndrome from other serious conditions, which may be concomitant and may require a different therapeutic approach.
- MeSH
- Immunotherapy adverse effects MeSH
- Humans MeSH
- Multiple Organ Failure etiology therapy MeSH
- Cytokine Release Syndrome * etiology therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
The disease severity of COVID-19, especially in the elderly and patients with co-morbidities, is characterized by hypercytokinemia, an exaggerated immune response associated with an uncontrolled and excessive release of proinflammatory cytokine mediators (cytokine storm). Flavonoids, important secondary metabolites of plants, have long been studied as therapeutic interventions in inflammatory diseases due to their cytokine-modulatory effects. In this review, we discuss the potential role of flavonoids in the modulation of signaling pathways that are crucial for COVID-19 disease, particularly those related to inflammation and immunity. The immunomodulatory ability of flavonoids, carried out by the regulation of inflammatory mediators, the inhibition of endothelial activation, NLRP3 inflammasome, toll-like receptors (TLRs) or bromodomain containing protein 4 (BRD4), and the activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2), might be beneficial in regulating the cytokine storm during SARS-CoV-2 infection. Moreover, the ability of flavonoids to inhibit dipeptidyl peptidase 4 (DPP4), neutralize 3-chymotrypsin-like protease (3CLpro) or to affect gut microbiota to maintain immune response, and the dual action of angiotensin-converting enzyme 2 (ACE-2) may potentially also be applied to the exaggerated inflammatory responses induced by SARS-CoV-2. Based on the previously proven effects of flavonoids in other diseases or on the basis of newly published studies associated with COVID-19 (bioinformatics, molecular docking), it is reasonable to assume positive effects of flavonoids on inflammatory changes associated with COVID-19. This review highlights the current state of knowledge of the utility of flavonoids in the management of COVID-19 and also points to the multiple biological effects of flavonoids on signaling pathways associated with the inflammation processes that are deregulated in the pathology induced by SARS-CoV-2. The identification of agents, including naturally occurring substances such as flavonoids, represents great approach potentially utilizable in the management of COVID-19. Although not clinically investigated yet, the applicability of flavonoids against COVID-19 could be a promising strategy due to a broad spectrum of their biological activities.
- MeSH
- Anti-Inflammatory Agents pharmacology therapeutic use MeSH
- COVID-19 immunology MeSH
- COVID-19 Drug Treatment MeSH
- Flavonoids pharmacology therapeutic use MeSH
- Humans MeSH
- SARS-CoV-2 * MeSH
- Cytokine Release Syndrome drug therapy immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The FDA-approved drugs raloxifene and bazedoxifene could be among the best candidates to prevent mortality in severe COVID-19 patients. Raloxifene and bazedoxifene inhibit IL-6 signaling at therapeutic doses, suggesting they have the potential to prevent the cytokine storm, ARDS and mortality in severe COVID-19 patients, as is being shown with humanized antibodies blocking IL-6 signaling. In addition, raloxifene and bazedoxifene are selective estrogen receptor modulators with strong antiviral activity.
- MeSH
- Betacoronavirus drug effects pathogenicity MeSH
- Cytokines antagonists & inhibitors genetics MeSH
- Indoles pharmacology MeSH
- Interleukin-6 antagonists & inhibitors genetics MeSH
- Coronavirus Infections drug therapy genetics mortality virology MeSH
- Humans MeSH
- Pandemics MeSH
- Raloxifene Hydrochloride pharmacology MeSH
- Receptors, Estrogen antagonists & inhibitors MeSH
- Selective Estrogen Receptor Modulators pharmacology MeSH
- Signal Transduction drug effects MeSH
- Respiratory Distress Syndrome drug therapy prevention & control virology MeSH
- Pneumonia, Viral drug therapy genetics mortality virology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION AND OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the nasal cavity, penetrates the nasal epithelial cells through the interaction of its spike protein with the host cell receptor angiotensin-converting enzyme 2 (ACE2) and then triggers a cytokine storm. We aimed to assess the biocompatibility of fullerenol nanoparticles C60(OH)40 and ectoine, and to document their effect on the protection of primary human nasal epithelial cells (HNEpCs) against the effects of interaction with the fragment of virus - spike protein. This preliminary research is the first step towards the construction of a intranasal medical device with a protective, mechanical function against SARS-CoV-2 similar to that of personal protective equipment (eg masks). METHODS: We used HNEpCs and the full-length spike protein from SARS-CoV-2 to mimic the first stage of virus infection. We assessed cell viability with the XTT assay and a spectrophotometer. May-Grünwald Giemsa and periodic acid-Schiff staining served to evaluate HNEpC morphology. We assessed reactive oxygen species (ROS) production by using 2',7'-dichlorofluorescin diacetate and commercial kit. Finally, we employed reverse transcription polymerase chain reaction, Western blotting and confocal microscopy to determine the expression of angiotensin-converting enzyme 2 (ACE2) and inflammatory cytokines. RESULTS: There was normal morphology and unchanged viability of HNEpCs after incubation with 10 mg/L C60(OH)40, 0.2% ectoine or their composite for 24 h. The spike protein exerted cytotoxicity via ROS production. Preincubation with the composite protected HNEpCs against the interaction between the spike protein and the host membrane and prevented the production of key cytokines characteristic of severe coronavirus disease 2019, including interleukin 6 and 8, monocyte chemotactic protein 1 and 2, tissue inhibitor of metalloproteinases 2 and macrophage colony-stimulating factor. CONCLUSION: In the future, the combination of fullerenol and ectoine may be used to prevent viral infections as an intranasal medical device for people with reduced immunity and damaged mucous membrane.
- MeSH
- Amino Acids, Diamino MeSH
- Angiotensin-Converting Enzyme 2 metabolism MeSH
- COVID-19 * prevention & control MeSH
- Cytokines metabolism MeSH
- Epithelial Cells * drug effects virology MeSH
- Fullerenes * pharmacology chemistry MeSH
- Spike Glycoprotein, Coronavirus * metabolism MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Nanoparticles * chemistry MeSH
- Nasal Mucosa drug effects cytology MeSH
- Reactive Oxygen Species metabolism MeSH
- SARS-CoV-2 * drug effects MeSH
- Cytokine Release Syndrome * prevention & control MeSH
- Cell Survival * drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Kawasaki disease (KD) is a medium vessel systemic vasculitis that predominantly occurs in children below five years of age. It is an acute febrile condition in which coronary artery aneurysms and myocarditis are the most common cardiovascular complications. It is most often characterized by hypercytokinemia. The etiopathogenesis of KD is not fully understood. The present review synthesizes the recent advances in the pathophysiology and treatment options of KD. According to different studies, the genetic, infections and autoimmunity factors play a major role in pathogenesis. Several susceptibility genes (e.g. caspase 3) and cytokines (e.g. IL-2, IL-4, IL-6, IL-10, IFN-gamma and TNF-alpha) have been identified in KD. Patients with high cytokine levels are predisposed to KD shock syndrome. The importance of respiratory viruses in the pathogenesis of the disease is unclear. Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may induce in children and adults an abnormal systemic inflammatory response. This syndrome shares characteristics with KD. It has been called by many terms like MIS-C (Multisystem Inflammatory Syndrome in Children), PIMS-TS (pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2), hyperinflammatory shock syndrome, cytokine storm (cytokine release syndrome) or simply, Kawasaki-like syndrome. The cytokine's role in the development of KD or Kawasaki-like syndrome being triggered by COVID-19 is controversial. The presences of the antiendothelial cell autoantibodies (AECAs) together with the newly developed hypothesis of immunothrombosis are considered potential pathogenic mechanisms for KD. In consequence, the diagnosis and treatment of KD and Kawasaki-like syndrome, one of the most common causes of acquired heart disease in developed countries, are challenging without a clearly defined protocol.
COVID-19, a significant global health threat, appears to be an immune-related disease. Failure of effective immune responses in initial stages of infection may contribute to development of cytokine storm and systemic inflammation with organ damage, leading to poor clinical outcomes. Disease severity and the emergence of new SARS-CoV-2 variants highlight the need for new preventative and therapeutic strategies to protect the immunocompromised population. Available data indicate that these people may benefit from adoptive transfer of allogeneic SARS-CoV-2-specific T cells isolated from convalescent individuals. This review first provides an insight into the mechanism of cytokine storm development, as it is directly related to the exhaustion of T cell population, essential for viral clearance and long-term antiviral immunity. Next, we describe virus-specific T lymphocytes as a promising and efficient approach for the treatment and prevention of severe COVID-19. Furthermore, other potential cell-based therapies, including natural killer cells, regulatory T cells and mesenchymal stem cells are mentioned. Additionally, we discuss fast and effective ways of producing clinical-grade antigen-specific T cells which can be cryopreserved and serve as an effective "off-the-shelf" approach for rapid treatment of SARS-CoV-2 infection in case of sudden patient deterioration.
- MeSH
- COVID-19 * therapy MeSH
- Cytokines MeSH
- Humans MeSH
- SARS-CoV-2 * MeSH
- Cytokine Release Syndrome therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
CAR-T buněčná terapie, tedy terapie T-lymfocyty s chimérickým antigenovým receptorem (chimeric antigen receptor T-cells – CAR-T), původně vyvinutá pro léčbu hematologických malignit, ukazuje slibné výsledky i u refrakterních systémových autoimunitních revmatických onemocnění (SARD). CAR-T terapie cílí na B-lymfocyty, které hrají klíčovou roli v autoimunitních procesech. Pilotní klinické zkoušky s CAR-T terapií u pacientů se SLE, systémovou sklerodermií a antisyntetázovým syndromem vedly k významnému zlepšení klinického stavu pacientů, vymizení autoprotilátek a dosažení remise bez nutnosti jiné imunosupresivní léčby. CAR-T terapie přináší ale i určitá rizika, jako je syndrom uvolňování cytokinů (CRS) nebo neurotoxické nežádoucí účinky. Výzvu do budoucna představují vysoké náklady a složitost výroby CAR-T-buněk.
CAR-T cell therapy, which involves T lymphocytes engineered with a chimeric antigen receptor (CAR-T), was initially developed for treating hematologic malignancies. However, it has also shown promising results in refractory systemic autoimmune rheumatic diseases (SARD). CAR-T therapy targets B lymphocytes, which play a crucial role in autoimmune processes. Preliminary clinical trials in patients with systemic lupus erythematosus, systemic sclerosis, and antisynthetase syndrome have demonstrated significant clinical improvement, disappearance of autoantibodies, and the achievement of remission without the need for other immunosuppressive therapies. Nonetheless, CAR-T therapy also carries certain risks, such as cytokine release syndrome and neurotoxic side effects. Future challenges include the high costs and complexity of CAR-T cell production.
- MeSH
- Autoimmune Diseases drug therapy classification MeSH
- Immunotherapy, Adoptive * classification methods MeSH
- Humans MeSH
- Rheumatic Diseases * drug therapy classification MeSH
- Cytokine Release Syndrome diagnosis etiology immunology MeSH
- T-Lymphocytes immunology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Infection with the SARS-CoV-2 virus (COVID-19 disease) can cause a wide range of clinical situations - from an asymptomatic state to fatal outcomes. In cases of serious clinical manifestations, the underlying mechanisms involve a number of immune cells and stromal cells as well as their products such as pro-inflammatory interleukin-6 and tumour necrosis factor-alpha that ultimately cause the cytokine storm. The situation of overproduction of pro-inflammatory cytokines is somewhat similar to, though in a mild form, health conditions in obesity and related metabolic disorders like type-2 diabetes, which are also considered important risk factors for severe illness in COVID-19. Interestingly, neutrophils perhaps play a significant role in this pathogenesis. On the other hand, it is thought that COVID-19-related critical illness is associated with pathological hyperactivity of the complement system and coagulopathy. Although the precise molecular interactions between the complement and coagulation systems are not clear, we observe an intimate cross-talk between these two systems in critically ill COVID-19 patients. It is believed that both of these biological systems are connected with the cytokine storm in severe COVID-19 disease and actively participate in this vicious cycle. In order to hinder the pathological progression of COVID-19, a number of anticoagulation agents and complement inhibitors have been used with varying success. Among these drugs, low molecular weight heparin enoxaparin, factor Xa inhibitor apixaban, and complement C5 inhibitor eculizumab have been commonly used in patients with COVID-19. Our overall experience might help us in the future to tackle any such conditions.
- MeSH
- COVID-19 * MeSH
- Cytokines MeSH
- Immunologic Factors MeSH
- Complement Inactivating Agents MeSH
- Complement C5 MeSH
- Humans MeSH
- Prognosis MeSH
- SARS-CoV-2 MeSH
- Cytokine Release Syndrome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Infekce SARS-CoV-2 může vyvolat nadměrnou produkci prozánětlivých cytokinů způsobujících rozvoj cytokinové bouře. SARS-CoV-2 indukuje nekontrolovanou odpověď nespecifické imunity a oslabuje specifické imunitní reakce, čímž způsobuje poškození tkání. Pochopení mechanismů nespecifické a specifické imunity indukované SARS-CoV-2 je zásadní pro predikci vývoje onemocnění azavedení účinných opatření pro efektivní kontrolu šíření viru. Podrobně jsou diskutovány reakce imunitního systému a klíčové imunopatogenetické mechanismy onemocnění covid-19.
he SARS-CoV-2 infection can induce an excessive production of pro-inflammatory cytokines causing the cytokine storm syndrome. The uncontrolled nonspecific immune response and the specific immune responses impairment induced by SARS-CoV-2 eventually result in the tissue damage. Understanding the mechanisms of non-specific and specific immunity induced by SARS-CoV-2 is essential to be able to predict the disease outcome and to develop effective strategies to control the virus spread. Reactions of the immune system and the key immunopathogenetic mechanisms involved in covid-19 disease are discussed.
- MeSH
- Complement Activation immunology MeSH
- B-Lymphocytes immunology metabolism MeSH
- Killer Cells, Natural immunology metabolism MeSH
- COVID-19 * immunology physiopathology MeSH
- Dendritic Cells immunology metabolism MeSH
- Eosinophils immunology metabolism MeSH
- Hemostasis immunology MeSH
- Humans MeSH
- Lymphocytes immunology metabolism MeSH
- Mast Cells immunology metabolism MeSH
- Neutrophils immunology classification metabolism MeSH
- CD4-CD8 Ratio MeSH
- Eosinophil Granule Proteins immunology metabolism MeSH
- Immunity, Mucosal immunology MeSH
- Cytokine Release Syndrome physiopathology pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
