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Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1–18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov , NCT04340154 , and enrolment has ended. Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6–10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37–41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89–100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4–20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66–91), duration of remission was 80% (68–92), and disease-free survival was 80% (68–92) with transplantation censoring; overall survival was 96% (91–100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7–14) after CD19-directed and 12 days (10–15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

The first cases of COVID-19 were identified in China in 2019, and the disease subsequently spread rapidly around the world, leading it to be declared a pandemic. The disease affects the lungs through the upper and lower respiratory tracts, and with the development of pneumonia, a clinical picture leading to respiratory failure referred to as cytokine storm occurs as a result of excessive cytokine production associated with an excessive inflammatory immune response. The increase in inflammatory markers is related to acute respiratory distress syndrome, disseminated intravascular coagulation and hypercoagulation. We present here an explanation of cytokine storm and the associated immune damage mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 (coronavirus disease 2019) was first identified in China in December 2019 and is rapidly spreading worldwide as a pandemic. Since COVID-19 causes mild to severe acute respiratory syndrome, most studies in this context have focused on pathogenesis primarily in the respiratory system. However, evidence shows that the central nervous system (CNS) may also be affected by COVID-19. Since COVID-19 is spreading, it is necessary to study its possible cognitive effects on COVID-19 patients and their recovery. Methods: The articles used in this study were searched by keywords, such as cytokine storm and COVID-19, COVID-19 and executive dysfunction, cognitive disorder, and COVID-19, central nervous system (CNS) and COVID-19, coronavirus, neuroinvasion in Science Direct, Scopus, PubMed, Embase, and Web of Science databases based on preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist. The study evaluates all observational studies published between December 2019 and April 2021 in peer-reviewed journals, including cross-sectional, cohort, case-control studies, case reports, and case series. The search result was 106 articles, of which 73 articles related to COVID-19, the stages of infection by this virus, its effect on the nervous system and neurological symptoms, the cytokine storm caused by this infection, and the possible cognitive consequences caused by this virus in patients, has been reviewed. Other articles were not checked due to their limited relevance to the topic under discussion. Results: Studies showed that neurons may be directly affected by severe acute respiratory syndrome coronavirus (SARS-CoV)-1 and SARS-CoV-2. Furthermore, various studies indicated that systemic inflammation (so-called “cytokine storm”) is also responsible for brain damage induced by infection with SARS-CoV-1 and SARS-CoV-2. In such a way that these patients showed elevated levels of interleukin (IL-), 6, 8, and 10 and of tumor necrosis factor- alpha (TNF-α) in their blood. Conclusion: Various cognitive defects have been observed following an increased level of cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, 8. Therefore, due to the increased level of these pro-inflammatory factors in the brains of these patients, cognitive deficits can be expected, which need further investigation. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T (CAR‐T) cell therapy is highly effective in inducing complete remission in haematological malignancies. Severe cytokine release syndrome (CRS) is the most significant and life‐threatening adverse effect of this therapy. This multi‐centre study was conducted at six hospitals in China. The training cohort included 87 patients with multiple myeloma (MM), an external validation cohort of 59 patients with MM and another external validation cohort of 68 patients with acute lymphoblastic leukaemia (ALL) or non‐Hodgkin lymphoma (NHL). The levels of 45 cytokines on days 1–2 after CAR‐T cell infusion and clinical characteristics of patients were used to develop the nomogram. A nomogram was developed, including CX3CL1, GZMB, IL4, IL6 and PDGFAA. Based on the training cohort, the nomogram had a bias‐corrected AUC of 0.876 (95% CI = 0.871–0.882) for predicting severe CRS. The AUC was stable in both external validation cohorts (MM, AUC = 0.907, 95% CI = 0.899–0.916; ALL/NHL, AUC = 0.908, 95% CI = 0.903–0.913). The calibration plots (apparent and bias‐corrected) overlapped with the ideal line in all cohorts. We developed a nomogram that can predict which patients are likely to develop severe CRS before they become critically ill, improving our understanding of CRS biology, and may guide future cytokine‐directed therapies. [ABSTRACT FROM AUTHOR]

The RELIANCE study has demonstrated the activity and safety of relmacabtagene autoleucel (relma-cel) (JW Therapeutics [Shanghai] Co, Ltd, Shanghai, China), a CD19-targeted chimeric antigen receptor T-cell product, in patients with heavily pre-treated relapsed/refractory large B-cell lymphoma (r/r LBCL). This study aimed to report the updated 2-year data of the RELIANCE study. The RELIANCE study (NCT04089215) was an open-label, multi-center, randomized, phase 1/2 registrational clinical trial conducted at 10 clinical sites in China. Adult patients with heavily pre-treated r/r LBCL were enrolled and received lymphodepletion chemotherapy followed by infusion of 100 × 106 or 150 × 106 relma-cel. The primary endpoint was objective response rate (ORR) at 3 months, as assessed by investigators. Secondary endpoints were duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety profiles. From November 2017 to January 2022, a total of 68 patients were enrolled, and 59 patients received relma-cel infusion. As of March 29, 2022, a total of 59 patients had a median follow-up of 17.9 months (range, 0.3–25.6). ORR was 77.59% (95% confidence interval [CI], 64.73–87.49) and complete response rate was 53.45% (95% CI, 39.87–66.66). Median DoR was 20.3 months (95% CI, 4.86–not reached [NR]) and median PFS was 7.0 months (95% CI, 4.76–24.15). Median OS was NR and 1-year and 2-year OS rates were 75.0% and 69.3%, respectively. Three (5.1%) patients experienced grade ≥3 cytokine release syndrome and two (3.4%) patients had grade ≥3 neurotoxicity. The updated data of the RELIANCE study demonstrate durable response with and manageable safety profile of relma-cel in patients with heavily pre-treated r/r LBCL. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma remains incurable despite treatment advancements over the last 20 years. LCAR-B38M Cells in Treating Relapsed/Refractory Multiple Myeloma was a phase 1, first-in-human, investigator-initiated study in relapsed/refractory multiple myeloma conducted at four sites in China. The study used LCAR-B38M chimeric antigen receptor-T cells expressing two B-cell maturation antigen-targeting single-domain antibodies designed to confer avidity, and a CD3ζ signaling domain with a 4-1BB costimulatory domain to optimize T-cell activation and proliferation. This chimeric antigen receptor construct is identical to ciltacabtagene autoleucel. In the LEGEND-2 study (n = 57, Xi'an site), overall response rate was 88%; median (95% CI) progression-free survival and overall survival were 19.9 (9.6–31.0) and 36.1 (26.4–not evaluable) months, respectively; and median follow-up was 25 months. This case study reports on a patient with relapsed/refractory multiple myeloma (λ light chain type) who was treated with LCAR-B38M chimeric antigen receptor T cells in the LEGEND-2 study (Xi'an site); he had received five prior lines of treatment and had extensive extramedullary lesions. Case presentation: The patient, a 56-year-old Asian male, received cyclophosphamide (500 mg daily × 3 days) as lymphodepletion therapy and a total dose of 0.5 × 106 chimeric antigen receptor + T cells/kg split into three infusions (days 1, 24, and 84 from June to August 2016). He experienced grade 2 cytokine release syndrome after the first infusion; all symptoms resolved with treatment. No cytokine release syndrome occurred following the second and third infusions. His λ light chain levels decreased and normalized 20 days after the first infusion, and extramedullary lesions were healed as of January 2018. He has sustained remission for 5 years and received no other multiple myeloma treatments after LCAR-B38M chimeric antigen receptor T cell infusion. As of 30 October 2020, the patient is still progression-free and has maintained minimal residual disease-negative (10–4) complete response status for 52 months. Conclusions: This case provides support that treatment with LCAR-B38M chimeric antigen receptor T cells can result in long-term disease remission of 5 or more years without disease progression in a heavily pretreated patient with extensive extramedullary disease and no other treatment options. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a significant hematological malignancy in the United States, with a high mortality rate and limited treatment options. CAR T-cell therapy, a new and promising treatment, is being investigated for its efficacy and safety in AML. This meta-analysis aims to assess the safety and efficacy of CAR T-cell therapy in AML, considering various subgroups such as study location, study design, prior transplantation status, conditioning regimen, and CAR T-cell source. We conducted a comprehensive literature review across multiple databases, adhering to PRISMA guidelines and focusing on studies concerning CAR T-cell therapy in AML. We included original articles in English and excluded non-original reviews, abstracts, and non-English studies. The risk of bias was assessed using the Cochrane ROBINS-I tool. Statistical analysis involved meta-analysis with Cochrane's Q-test and I² statistic, using both fixed-effect and random-effects models, and assessed for publication bias. Our search yielded studies encompassing 57 AML patients treated with CAR T-cell therapy. The meta-analysis revealed a 48% incidence of complete remission with CAR T-cell therapy, varying significantly across subgroups based on study design, location, prior transplantation, conditioning regimen, and CAR T-cell source. The highest complete remission rates were observed in patients from China, those who had undergone prior hematopoietic cell transplantation, and those treated with fludarabine and cyclophosphamide conditioning regimen. Adverse events included graft-versus-host disease (7%) and cytokine release syndrome (53%). This meta-analysis highlights the potential of CAR T-cell therapy in AML treatment, especially when integrated with certain prior treatments and conditioning regimens. The findings suggest a higher efficacy in patients with previous hematopoietic cell transplantation and specific conditioning regimens. Further large-scale, randomized trials are essential to confirm these findings and establish CAR T-cell therapy as a standard treatment for AML. • Meta-analysis shows 48% AML remission rate with CAR T-cell therapy, varying by study specifics. • High remission in AML patients from China, with prior transplantation and specific regimens. • CAR T-cell therapy in AML linked to 7% graft-vs-host disease, 53% cytokine release syndrome. • Further trials needed to confirm CAR T-cell therapy as a standard AML treatment. [ABSTRACT FROM AUTHOR]

Background: LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods: LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results: As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions: The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) erupted in Hubei Province of China in December 2019 and has become a pandemic. Severe COVID-19 patients who suffer from acute respiratory distress syndrome (ARDS) and multi-organ dysfunction have high mortality. Several studies have shown that this is closely related to the cytokine release syndrome (CRS), often loosely referred to as cytokine storm. IL-6 is one of the key factors and its level is positively correlated with the severity of the disease. The molecular mechanisms for CRS in COVID-19 are related to the effects of the S-protein and N-protein of the virus and its ability to trigger NF-κB activation by disabling the inhibitory component IκB. This leads to activation of immune cells and the secretion of proinflammatory cytokines such as IL-6 and TNF-α. Other mechanisms related to IL-6 include its interaction with GM-CSF and interferon responses. The pivotal role of IL-6 makes it a target for therapeutic agents and studies on tocilizumab are already ongoing. Other possible targets of treating CRS in COVID-19 include IL-1β and TNF-α. Recently, reports of a CRS like illness called multisystem inflammatory syndrome in children (MIS-C) in children have surfaced, with a variable presentation which in some cases resembles Kawasaki disease. It is likely that the immunological derangement and cytokine release occurring in COVID-19 cases is variable, or on a spectrum, that can potentially be governed by genetic factors. Currently, there are no approved biological modulators for the treatment of COVID-19, but the urgency of the pandemic has led to numerous clinical trials worldwide. Ultimately, there is great promise that an anti-inflammatory modulator targeting a cytokine storm effect may prove to be very beneficial in reducing morbidity and mortality in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy has obtained promising results in relapsed or refractory multiple myeloma (R/R MM), while some patients do not response, or relapse in short term after treatment. Combining with anti-CD38 might solve the problem of targeting BCMA alone. We aimed to assess the efficacy and safety of BCMA and CD38 (BCMA-CD38) bispecific CAR-T cells in R/R MM patients. Methods: We did a single-center, single-arm clinical study at the Second Affiliated Hospital of Yangtze University in China. Patients meeting with the inclusion criteria were administered with fludarabine and cyclophosphamide before CAR-T cells infusion. Response and adverse events were assessed after infusion. This study was registered with the Chinese Clinical Trial Registration Center (ChiCTR1900026286). Results: First, we found BCMA-CD38 CAR-T cells exhibited enhanced killing effect on BCMA+CD38+ cells in vitro, compared to BCMA CAR-T and CD38 CAR-T cells. We further demonstrated its anti-tumor activity in vivo. Then, we enrolled 16 R/R MM patients for safety and efficacy analyses. Of the 16 evaluable patients, 14 (87.5%) respond to the treatment, including 13 stringent complete response (sCR) and one partial response (PR), while two patients did not respond. At a median follow-up of 11.5 months, of the 13 patients who achieved sCR, 76.9% (10/13) did not relapse or progress during follow-up. Relapse occurred in 3 patients (Patient 2, 3 and 4) after achieving sCR. In sum, four patients died, of which one died of hemophagocytic lymphohistiocytosis syndrome secondary to severe cytokine release syndrome (CRS) and three died of disease progression or relapse. The 1-year progression-free survival rates was 68.8%. The 1-year overall survival rate was 75.0%. Extramedullary lesions were eliminated in 62.5% (5/8) patients. The most common symptoms after CAR-T infusion were cytopenia (16, 100%), fever (10, 62.5%), fatigue (8, 50.0%) and myalgias (8, 50.0%). Twelve patients (75.0%) were observed with various grades of CRS, of which five patients (31.3%) got serious CRS (Grade ≥ 3). The CAR+ cell expansion levels were associated with the severity of CRS. Transient clonal isotype switch was observed after CAR-T infusion. Conclusion: Our results confirm that BCMA-CD38 CAR-T cells therapy is feasible in treating R/R MM patients, with high response rate, low recurrence rate and manageable CRS, which will be a promising treatment option for R/R MM. Trial registration: ChiCTR1900026286, registered on September 29, 2019, retrospectively registered, URL: https://www.chictr.org.cn/showproj.aspx?proj=43805 [ABSTRACT FROM AUTHOR]

The H7N9 influenza virus emerged in China in 2013, causing more than 1560 human infections, 39% of which were fatal. A 'cytokine storm' in the lungs of H7N9 patients has been linked to a poor prognosis and death; however, the underlying mechanism that triggers the cytokine storm is unknown. Here, we found that efficient replication of the H7N9 virus in mouse lungs activates gasdermin E (GSDME)-mediated pyroptosis in alveolar epithelial cells, and that the released cytosolic contents then trigger a cytokine storm. Knockout of Gsdme switched the manner of death of A549 and human primary alveolar epithelial cells from pyroptosis to apoptosis upon H7N9 virus infection, and Gsdme knockout mice survived H7N9 virus lethal infection. Our findings reveal that GSDME activation is a key and unique mechanism for the pulmonary cytokine storm and lethal outcome of H7N9 virus infection and thus opens a new door for the development of antivirals against the H7N9 virus. [ABSTRACT FROM AUTHOR]

In the Wuhan province of China, almost two years ago, in December 2019, the novel Coronavirus 2019 has caused a severe involvement of the lower respiratory tract leading to an acute life-threatening respiratory syndrome, coronavirus disease-19 (COVID-19). Subsequently, coronavirus 2 (SARS-CoV-2) rapidly spread to the entire world causing a pandemic and affected every single person on earth either directly or indirectly with destroying all facets of social life and economy. Since the announcement of COVID-19 as a global pandemic, we have witnessed tremendous scientific work on all aspects of COVID-19 across the globe, which has never been witnessed before. The most remarkable achievement would be the introduction of vaccines, which provide protection from the severe infection and is the only premise for the control of disease. However, despite the tremendous work, the number of treatments either antiviral or immunomodulatory for infected patients are considerably limited, yet disease is causing substantial morbidity and mortality. COVID-19 follows heterogenous disease course among infected individuals, and dysregulated immune system is primarily responsible for the worse outcomes. Immune deficiency, being on corticosteroids for inflammatory diseases, delayed interferon response and advanced age adversely influence prognosis with impairing viral clearance. On the other hand, exuberant immune response with features of cytokine storm is the leading cause of death, which can be alleviated by use of either general immunosuppression with corticosteroids or selective neutralization of potent pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6. Herein, we summarized the potential effective immunomodulatory treatments emphasizing in which patient population it is the most suitable, which dose should be administered, and which is the most appropriate timepoint to administer the drug during the course of the disease. [ABSTRACT FROM AUTHOR]

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a zoonotic virus which was first discovered in Wuhan, the People's Republic of China in December 2019 and has led to one of the greatest pandemics of world history in a short period of time 1. SARS-CoV-2 is a rapidly spreading infectious disease with a high mortality rate. The disease has a moderate and severe course in approximately 20% of the patients and mortality reaches up to 62% among these patients 2. The majority of the patients develop SARS-CoV-2-induced pneumonia and manifestations of pneumonia rapidly progress to respiratory failure. In severe Covid pneumonia, it has been demonstrated that increased plasma concentrations of cytokines including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-12 are involved in immune response and in cytokine storm caused by the increase in these cytokines lead to mortality1, 3. Tocilizumab (TCZ) is a promising agent that is used for the treatment of cytokine storm. TCZ is an IgG1 class recombinant humanized monoclonal antibody against IL-6 receptor 3. It has then been used for the treatment of rheumatic diseases. Due to its mechanism of action, TCZ treatment comes to the forefront particularly in cases of severe COVID-19-induced cytokine pneumonia presenting with cytokine storm 3. However, potential IgE-mediated immunological reactions against this drug, especially anaphylaxis, may deprive these patients of an important treatment option for the treatment of COVID-19-induced cytokine storm. Although TCZ-induced anaphylaxis has been reported as case reports of indicated rheumatic diseases, TCZ-induced anaphylaxis has not yet been reported in patients using TCZ for SARS-CoV-2-induced cytokine storms 4. In this case series, we aimed to represent cases of anaphylaxis which developed in two different patients using TCZ for SARS-CoV-2-induced cytokine storm. [ABSTRACT FROM AUTHOR]

Studies from China on COVID‐19 revealed that nonsurvivors had cytokine storm with high IL‐6 and hyperferritinemia. Iron liberated from necrotic cells may catalyze free radical production and amplify lipid peroxidation causing membrane dysfunction and multiorgan failure. Consequently, iron chelators have been successfully utilized in various experimental and clinical models of cytokine storm and multiorgan damage, such as in ischemia‐reperfusion injury, sepsis, and infections. Since viral replication may be influenced by iron accumulation, iron chelation has been proven beneficial in a variety of viral infections, such as HIV‐1, hepatitis B virus, Mengovirus, Marburg hemorrhagic fever, Enterovirus 71, and West Nile virus. In this commentary, we elaborate on the idea of considering iron chelation as a therapeutic modality in patients with severe COVID‐19 infection. For critically ill patients in the ICU, intravenous deferoxamine would provide sufficient and rapid iron chelation to ameliorate cytokine storm, whereas in less severe cases an oral chelator could prevent the development of excessive inflammatory response. [ABSTRACT FROM AUTHOR]

Since December 2019, the world has experienced the emergence in China of a new infection called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This infection quickly has progressed to a global pandemic since March 2020, with very high human-to-human transmission rate. Besides lung injury, COVID-19 is also associated with cardio and neurovascular complications. Herein, we report the case of a 77-year-old female who presented with non-severe COVID-19 and multiple ischemic strokes secondary to an extensive carotid thrombosis. The ischemic stroke was supposed to have been caused by the cytokine storm related to COVID-19. The possibility of hemorrhagic transformation, based on the assessment of bleeding score, limited the use of anticoagulation, and probably explained the stroke recurrence and poor outcome in our patient. The pathogenic mechanism and the management of this complex situation are still lacking and further studies are needed. [ABSTRACT FROM AUTHOR]

Introduction: Coronavirus disease 2019 (COVID-19) appeared in China in December 2019 and has spread around the world. High Interleukin-6 (IL-6) levels in COVID-19 patients suggest that a cytokine storm may play a major role in the pathophysiology and are considered as a relevant parameter in predicting most severe course of disease. The aim of this study was to assess repeated IL-6 levels in critically ill COVID-19 patients admitted to our Intensive Care Unit (ICU) and to evaluate their relationship with patient's severity and outcome. Methods: We conducted a retrospective study on patients admitted to the ICU with a diagnosis of COVID-19 between March 10 (i.e. the date of the first admitted patients) and April 30, 2020. Demographic, clinical and laboratory data were collected at admission. On the day of IL-6 blood concentration measurement, we also collected results of D-Dimers, C-Reactive Protein, white blood cells and lymphocytes count, lactate dehydrogenase (LDH) and ferritin as well as microbiological samples, whenever present. Results: Of a total of 65 patients with COVID-19 admitted to our ICU we included 41 patients with repeated measure of IL-6. There was a significant difference in IL-6 levels between survivors and non-survivors over time (p = 0.001); moreover, non survivors had a significantly higher IL-6 maximal value when compared to survivors (720 [349–2116] vs. 336 [195–646] pg/mL, p = 0.01). The IL-6 maximal value had a significant predictive value of ICU mortality (AUROC 0.73 [95% CI 0.57–0.89]; p = 0.01). Conclusions: Repeated measurements of IL-6 can help clinicians in identifying critically ill COVID-19 patients with the highest risk of poor prognosis. [ABSTRACT FROM AUTHOR]

Corona virus disease 2019 (COVID-19) patients with severe immune abnormalities are at risk of cytokine release syndrome (CRS). The definition, prevention, and treatment of symptoms of CRS in critically ill patients with COVID-19 are important problems. We report a single-center case series of 11 COVID-19 patients with acute respiratory distress syndrome from The First Affiliated Hospital of Guangzhou Medical University in China from 26 January 2020 to 18 February 2020. The termination date of follow-up was 19 February 2020. Eight patients were determined to have characteristics of CRS, including pulmonary inflammation, fever, and dysfunction of nonpulmonary organs. An increase in interleukin-6 in peripheral blood was the highest risk factor and an early indicator of CRS in COVID-19. [ABSTRACT FROM AUTHOR]

In December 2019, a cluster of pneumonia caused by a novel coronavirus (2019-nCoV), officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, Hubei province, China. Cytokine storm is an uncontrolled systemic inflammatory response resulting from the release of large amounts of pro-inflammatory cytokines and chemokines that occurs at phase 3 of viral infection. Such emergence led to the development of many clinical trials to discover efficient drugs and therapeutic protocols to fight with this single-stranded RNA virus. Corticosteroids suppress inflammation of the lungs during the cytokine storm, weaken immune responses, and inhibit the elimination of pathogen. For this reason, in COVID-19 corticosteroid therapy, systemic inhibition of inflammation is observed with a wide range of side effects. The present review discusses the effectiveness of the corticosteroid application in COVID-19 infection and the related side effects of these agents. In summary, a number of corticosteroids, including and especially methylprednisolone and dexamethasone, have demonstrated remarkable efficacy, particularly for COVID-19 patients who underwent mechanical ventilation. [ABSTRACT FROM AUTHOR]

Background Although the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in respiratory specimens has been widely used to diagnose coronavirus disease 2019 (COVID-19), it is undeniable that serum SARS-CoV-2 nucleic acid (RNAemia) could be detected in a fraction of COVID-19 patients. However, it is not clear whether testing for RNAemia is correlated with the occurrence of cytokine storms or with the specific class of patients. Methods This study enrolled 48 patients with COVID-19 admitted to the General Hospital of Central Theater Command, People's Liberation Army, a designated hospital in Wuhan, China. The patients were divided into 3 groups according to the Diagnosis and Treatment of New Coronavirus Pneumonia (sixth edition) guidelines issued by the National Health Commission of China. Clinical and laboratory data were collected, and the serum viral load and interleukin 6 (IL-6) level were determined. Results Analysis of clinical characteristics of 48 cases of COVID-19 showed that RNAemia was diagnosed only in the critically ill group and seemed to reflect the severity of the disease. Furthermore, the level of the inflammatory cytokine IL-6 in critically ill patients increased significantly, almost 10 times that in other patients. More importantly, the extremely high IL-6 level was closely correlated with the detection of RNAemia (R = 0.902). Conclusions Detectable serum SARS-CoV-2 RNA (RNAemia) in patients with COVID-19 was associated with elevated IL-6 concentration and poor prognosis. Because elevated IL-6 may be part of a larger cytokine storm that could worsen outcome, IL-6 could be a potential therapeutic target for critically ill patients with an excessive inflammatory response. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new pandemic infectious disease that originated in China. COVID-19 is a global public health emergency of international concern. COVID-19 causes mild to severe illness with high morbidity and mortality, especially in preexisting risk groups. Therapeutic options are now limited to COVID-19. The hallmark of COVID-19 pathogenesis is the cytokine storm with elevated levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor-alpha (TNF-α), chemokine (C-C-motif) ligand 2 (CCL2), and granulocyte-macrophage colony-stimulating factor (GM-CSF). COVID-19 can cause severe pneumonia, and neurological disorders, including stroke, the damage to the neurovascular unit, blood-brain barrier disruption, high intracranial proinflammatory cytokines, and endothelial cell damage in the brain. Mast cells are innate immune cells and also implicated in adaptive immune response, systemic inflammatory diseases, neuroinflammatory diseases, traumatic brain injury and stroke, and stress disorders. SARS-CoV-2 can activate monocytes/macrophages, dendritic cells, T cells, mast cells, neutrophils, and induce cytokine storm in the lung. COVID-19 can activate mast cells, neurons, glial cells, and endothelial cells. SARS-CoV-2 infection can cause psychological stress and neuroinflammation. In conclusion, COVID-19 can induce mast cell activation, psychological stress, cytokine storm, and neuroinflammation. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) caused by "Severe Acute Respiratory Syndrome Coronavirus-2" (SARS-CoV-2) infection emerged in Wuhan, a city of China, and spread to the entire planet in early 2020. The virus enters the respiratory tract cells and other tissues via ACE2 receptors. Approximately 20% of infected subjects develop severe or critical disease. A cytokine storm leads to over inflammation and thrombotic events. The most common clinical presentation in COVID-19 is pneumonia, typically characterized by bilateral, peripheral, and patchy infiltrations in the lungs. However multi-systemic involvement including peripheral thromboembolic skin lesions, central nervous, gastrointestinal, circulatory, and urinary systems are reported. The disease has a higher mortality compared to other viral agents causing pneumonia and unfortunately, no approved specific therapy, nor vaccine has yet been discovered. Several clinical trials are ongoing with hydroxychloroquine, remdesivir, favipiravir, and low molecular weight heparins. This comprehensive review aimed to summarize coagulation abnormalities reported in COVID-19, discuss the thrombosis, and inflammation-driven background of the disease, emphasize the impact of thrombotic and inflammatory processes on the progression and prognosis of COVID-19, and to provide evidence-based therapeutic guidance, especially from antithrombotic and antiinflammatory perspectives. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is caused by a novel form of the coronavirus that caused severe acute respiratory syndrome (SARS). SARS-CoV-2 raised in China and has broadcast to 261 countries globally. SARS-CoV-2 a member of β-coronavirus family and has an almost matching genome sequence to a bat coronavirus, pointing to the bat as the natural host before it was transmitted to humans. SARS-CoV-2 uses the same receptor, angiotensinconverting enzyme 2 (ACE2) as that used by SARS-CoV and principally infects the respiratory tract. The clinical symptoms of COVID-19 patients include fever, cough and fatigue whilst small populations of patients have gastrointestinal symptoms. The old people and people with underlying metabolic and cardiovascular diseases are more affected to infection and have worse outcomes. These may be associated with acute respiratory distress syndrome (ARDS) and a cytokine storm. In this review, we discuss the pathogenesis and clinical characteristics of disease and the pharmacologic approaches that may control COVID-19. [ABSTRACT FROM AUTHOR]

• Epidemiology of COVID-19 and life cycle of SARS-CoV-2 in human cells was explored. • SARS-CoV-2-induced cell-mediated immunity plays a critical role in COVID-19. • SARS-CoV-2 infection induces immune cell-mediated cytokine storms that promote pulmonary fibro-inflammation and organ failure. • This study highlights the immunotherapeutic effects of IL-15 on innate immunity to promote the clearance of SARS-CoV-2 viral loads. Coronavirus disease 2019 (COVID-19) is a pulmonary inflammatory disease induced by a newly recognized coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection was detected for the first time in the city of Wuhan in China and spread all over the world at the beginning of 2020. Several millions of people have been infected with SARS-CoV-2, and almost 382,867 human deaths worldwide have been reported so far. Notably, there has been no specific, clinically approved vaccine or anti-viral treatment strategy for COVID-19. Herein, we review COVID-19, the viral replication, and its effect on promoting pulmonary fibro-inflammation via immune cell-mediated cytokine storms in humans. Several clinical trials are currently ongoing for anti-viral drugs, vaccines, and neutralizing antibodies against COVID-19. Viral clearance is the result of effective innate and adaptive immune responses. The pivotal role of interleukin (IL)-15 in viral clearance involves maintaining the balance of induced inflammatory cytokines and the homeostatic responses of natural killer and CD8+ T cells. This review presents supporting evidence of the impact of IL-15 immunotherapy on COVID-19. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 is a novel coronavirus that was initially described in Wuhan China in December 2019. In the USA (US), the person to be diagnosed with the novel Coronavirus infection (COVID) was on 19 January 2020. On 18 March 2020, a 31-year-old morbidly obese African American woman presented with severe dyspnea with associated hypoxemia, fever and bilateral interstitial pulmonary ground glass infiltrates consistent with viral pneumonitis. Nasopharyngeal PCR testing was positive for SARS-CoV-2. Despite initiation of hydroxychloroquine and azithromycin along with supplemental oxygen therapy, rapid disease progression consistent with cytokine release syndrome ensued, leading to initiation of mechanical ventilatory support. Anti-Interleukin (IL)-6 receptor monoclonal antibody (tocilizumab) was administered. Acute respiratory distress syndrome (ARDS) leads to refractory hypoxemia and demise. Severe morbid obesity as well as race may be unidentified risk factors for the development of severe Illness in patients with COVID-19. [ABSTRACT FROM AUTHOR]

Since December 2019, a novel coronavirus pneumonia (COVID-19) has broken out in Wuhan, China and spread rapidly. Recent studies have found that ⁓ 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. IL-6 is one of the key cytokines involved in infection-induced cytokine storm. Tocilizumab, which is the IL-6 receptor antagonist, has been approved by the US FDA for the treatment of cytokine release syndrome (CRS), is expected to treat cytokine storm caused by COVID-19 and is now in clinical trials. In this paper, we will elaborate the role of cytokine storm in COVID-19, the mechanism of tocilizumab on cytokine storm and the key points of pharmaceutical care based on the actual clinical application for COVID-19 in our hospital, the latest research reports, clinical trial progress of tocilizumab, drug instruction from the US FDA, and "Diagnosis and Treatment Plan of Novel Coronavirus Pneumonia (seventh trial edition)" in China, so as to provide reference for the treatment of COVID-19. [ABSTRACT FROM AUTHOR]

A previous study suggested that the condition of 11 (11%) patients worsened in a short period of time and they died of multiple organ failure [[2]], while Wang et al. [[3]] reported that 4.3% of COVID-19 cases were fatal. A national study of 1099 patients with COVID-19 found that 55 patients (5%) were admitted to an intensive care unit and 15 (1.36%) succumbed to the infection [[4]]. All data are medians and interquartile ranges (IQR), with dot plots representing all values In summary, COVID-19 mortality is more common in older male patients with comorbidities and is mainly caused by multiple organ dysfunction syndrome. Tocilizumab (a monoclonal antibody targeting the interleukin-6 receptor) had been used to treat cytokine storm syndrome [[10]], and a clinical trial to assess its use in COVID-19 patients has been registered. [Extracted from the article]

Rapidly spreading outbreak of the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is causing serious health concerns worldwide. It started as an epidemic in Wuhan, Hubei province, central China, and has now become a pandemic, spreading over most of the continents of the planet. The major clinical symptoms of the infection are dry cough, fever, pneumonia, respiratory failure, hypoxia, and in certain cases, even death. Alveolar damage and respiratory system failure are observed in severe cases. Initial mild infection leads to activation of the immune system in the lungs and accumulation of various inflammatory cells and molecules. At a later phase during the infection, a "cytokine storm" causes an Acute Respiratory Distress Syndrome (ARDS), leading to an increase in the production of pro-inflammatory cytokines, migration of a large number of immune cells to the site of infection, and ultimately pulmonary damage. The rapid and uncontrolled outbreak requires putative therapeutic drugs for treatment of patients suffering from COVID-19. Amongst the currently used antiviral drugs, such as hydroxychloroquine, lopinavir, remdesivir etc. we would like to present an update on another effective drug, pentoxifylline. Pentoxifylline has anti-inflammatory, immunomodulatory, anti-viral, and bronchodilatory properties. Pentoxifylline is known to reduce cytokine production, immune cell migration, and suppress certain signal transduction pathways (e.g. NF-ĸβ and STAT3). Thus, it minimizes inflammatory damage in the lung tissues. [ABSTRACT FROM AUTHOR]

Rapidly spreading outbreak of the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is causing serious health concerns worldwide. It started as an epidemic in Wuhan, Hubei province, central China, and has now become a pandemic, spreading over most of the continents of the planet. The major clinical symptoms of the infection are dry cough, fever, pneumonia, respiratory failure, hypoxia, and in certain cases, even death. Alveolar damage and respiratory system failure are observed in severe cases. Initial mild infection leads to activation of the immune system in the lungs and accumulation of various inflammatory cells and molecules. At a later phase during the infection, a “cytokine storm” causes an Acute Respiratory Distress Syndrome (ARDS), leading to an increase in the production of pro-inflammatory cytokines, migration of a large number of immune cells to the site of infection, and ultimately pulmonary damage. The rapid and uncontrolled outbreak requires putative therapeutic drugs for treatment of patients suffering from COVID-19. Amongst the currently used antiviral drugs, such as hydroxychloroquine, lopinavir, remdesivir etc. we would like to present an update on another effective drug, pentoxifylline. Pentoxifylline has anti-inflammatory, immunomodulatory, anti-viral, and bronchodilatory properties. Pentoxifylline is known to reduce cytokine production, immune cell migration, and suppress certain signal transduction pathways (e.g. NF-κβ and STAT3). Thus, it minimizes inflammatory damage in the lung tissues. [ABSTRACT FROM AUTHOR]

The global spread of COVID-19 has caused a substantial societal burden and become a major global public health issue. The COVID-19 elderly population with hypertension, diabetes, cardiovascular, and cerebrovascular diseases are at risk. Mortality rates are highest in these individuals if infected with COVID-19. Although the lungs are the main organs involved in acute respiratory distress syndrome caused by COVID-19 infection, COVID-19 triggers inflammatory and immune mechanisms, inducing a "cytokine storm" that aggravates disease progression and may lead to death. Presently, effective drugs are lacking, although current studies have confirmed that drugs with therapeutic potential include redaciclovir, lopinavir/ritonavir combined with interferon-β, convalescent plasma, and monoclonal antibodies. Currently, the most reasonable and effective way to prevent COVID-19 is to control the source of infection, terminate routes of transmission, and protect susceptible populations. With the rise of COVID-19 in China and worldwide, further prevention, diagnosis, and treatment measures are a critical unmet need. Cerebrovascular disease has high incidence, disability rate, and fatality rate. COVID-19 patient outcomes may also be complicated with acute stroke. This paper summarizes the influence of COVID-19 on cerebrovascular disease and discusses possible pathophysiological mechanisms to provide new angles for the prevention and diagnosis of this disease. [ABSTRACT FROM AUTHOR]

In December 2019, a novel coronavirus (SARS-CoV-2) was identified as the cause of clustered pneumonia cases in Wuhan, a city in the Hubei Province of China. The virus rapidly spread to the rest of the world after a huge epidemic in China and WHO has declared a pandemic on March 11, 2020. SARS-CoV-2 is transmitted via respiratory droplets and fomites during close unprotected contact. The airborne spread has not been established as a major route of transmission. The mean incubation period of the illness is 5 days and it mainly presents with fever and respiratory symptoms. Myalgia, loss of taste and smell, diarrhea and dermatological findings are also common during the course of the disease. Laboratory findings are nonspecific. Significant elevations in inflammation markers can be observed in some patients due to cytokine storm. Typical CT findings are bilateral ground glass opacities and consolidation with peripheral and lower lobes distribution. COVID-19 causes mild symptoms in most cases, however it may progress to severe pneumonia leading to ARDS and death, especially in those with advanced age and comorbid diseases. There is no specific effective antiviral treatment for COVID-19. A number of in vitro effective agents have been identified. These agents such as chloroquine phosphate/hydroxychloroquine, favipiravir, remdesivir, lopinavir/ritonavir are widely used in the treatment of the disease. Convalescent plasma therapy and the cytokine inhibitory agents such as tocilizumab, used to treat disease-induced cytokine storm, are particularly preferred in the treatment severe cases. [ABSTRACT FROM AUTHOR]

In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked a pandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses singlestranded positive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteins that are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate and adaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcome of the COVID-19 might be associated with the excessive production of proinflammatory cytokines "cytokine storm" leading to an acute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, is still uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such as hydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatment choices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatory treatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, the host immune response against SARS-CoV-2 and its association with the cytokine storm. [ABSTRACT FROM AUTHOR]

BACKGROUND: In recent years, tumor immunotherapy has developed rapidly. Most scholars have focused on the single antibody treatment with autologous chimeric antigen receptor T-cell (CAR-T), but poor quality and small number of cultured cells are encountered. Therefore, allogeneic CAR-T cells have a better developmental potential. OBJECTIVE: To investigate the efficacy and safety of allogeneic CAR-T cells in the treatment of recurrent leukemia after allogeneic hematopoietic stem cell transplantation. METHODS: Two patients with relapsed refractory chronic myeloid leukemia in lymphoid blast crisis after allogeneic hematopoietic stem cell transplantation were treated with allogeneic CAR-T cells. Their clinical data were analyzed and relevant literature was reviewed. RESULTS AND CONCLUSION: Case 1 was hospitalized because of fever and fatigue for 5 days, and was diagnosed as chronic myeloid leukemia in lymphoid blast crisis by bone marrow cell morphology, flow cytometry, chromosome analysis, fusion gene and other related examinations. After oral imatinib combined with low dose chemotherapy, HLA10/10 matched haploid transplantation from daughter to mother proceeded smoothly. Three months after transplantation, BCR-ABL (p210) was positive, and chimera: donor cells accounted for 67.4%. After treatment with fludarabine+cyclophosphamide regimen, anti-CD19 CAR-T cells were infused at a dose of 5 ×106 cells/kg. Two weeks later, BCR-ABL (p210) turned negative and chimera: donor cells accounted for 99.62%. During the period, cytokine release syndrome level 1 appeared and symptomatic treatment was performed. The follow-up lasted for 6 months. Case 2 was treated in the local hospital in April 2011 because of left upper abdomen fullness for 1 year and night sweat for 15 days. One year later, it progressed to chronic myeloid leukemia in lymphoid blast crisis with T315I mutation. HLA 7/10 matched haploid stem cell transplantation from little brother to brother was performed after remission by chemotherapy. Anti-CD19 CAR-T cells were transfused at 2×105/kg in the second relapse in 2018. During this period, cytokine release syndrome level 4 appeared. Chronic myeloid leukemia continued to alleviate for over 2 months and then relapsed resulting in death. Thus, the donor-derived CAR-T cells can be considered for the treatment of recurrent chronic myeloid leukemia in lymphoid blast crisis after allogeneic hematopoietic stem cell transplantation. It can be transfused repeatedly. It is safe and effective, and the incidence of Graft-versus-host disease is low. Sequential treatment with anti-CD22 CAR-T cells is safe and effective. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the pathophysiology of certain autoimmune diseases, particularly, anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5þ DM). Topics covered include the association of anti-MDA5þ DM to rapidly progressive interstitial lung disease (RP-ILD), the prevalence of anti-MDA5 antibody (Ab), and the clinical features of anti-MDA5þ DM.

One of the most perplexing questions regarding the current COVID-19 coronavirus epidemic is the discrepancy between the severity of cases observed in the Hubei province of China and those occurring elsewhere in the world. One possible answer is antibody dependent enhancement (ADE) of SARS-CoV-2 due to prior exposure to other coronaviruses. ADE modulates the immune response and can elicit sustained inflammation, lymphopenia, and/or cytokine storm, one or all of which have been documented in severe cases and deaths. ADE also requires prior exposure to similar antigenic epitopes, presumably circulating in local viruses, making it a possible explanation for the observed geographic limitation of severe cases and deaths. [ABSTRACT FROM AUTHOR]

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19. [ABSTRACT FROM AUTHOR]

The outbreak of coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has emerged in China in December 2019 and rapidly spread to more than 196 countries worldwide. The physiopathology of human SARS-CoV-2 has not been completely understood, but its pathogenesis has been linked to a disproportionate response of the immune system. Just as described for SARS and MERS, an uncontrolled systemic inflammatory response, known as cytokine release syndrome (CRS) was observed in severe COVID-19 patients. It results from the release by immune and non-immune effector cells of substantial amounts of pro-inflammatory cytokines and appears to contribute to SARS-CoV-2 pulmonary inflammation and extensive lung damage. In addition, hyper-coagulation and thrombosis resulted from the important release of pro-inflammatory cytokines contribute to the lethality of subjects severely infected with SARS-CoV-2. It is therefore essential to have a deep understanding of the various cytokines involved in this exacerbated immune response, and that could be targeted by potential immunological treatments. The aim of this review was to gather the current knowledge about the role of pro-inflammatory cytokines, namely IL-1β, IL-6, IL-8, IL-17 and TNFα in SARS-CoV-2 CRS , the probable causes and clinical outcomes of this phenomenon in severe cases of COVID-19. • SARS-CoV-2 infection is associated with an exacerbated inflammatory responses. • IL-6, IL-1β, TNF-α, IL-17, IL-8 are involved in COVID19 cytokine release syndrome. • Cytokines exacerbation participates in thrombo-embolism associated with poor outcome. • CRS may be due to pyroptosis, microbiota alteration or delayed IFN response. [ABSTRACT FROM AUTHOR]

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19. [Display omitted] • Detailed COVID-19 immune landscape depicted by integrated 1.46 million single cells • Peripheral immune subtypes differentially associated with distinct clinical features • SARS-CoV-2 RNA is present in diverse epithelial and immune cells • Megakaryocytes and monocyte subsets may contribute to cytokine storms Analysis of the immune landscape in the lung and peripheral blood of COVID patients across different regions in China at the single-cell level documents the presence of viral RNAs in diverse cell types and highlights the potential contribution of megakaryocytes and monocyte subsets to cytokine storms. [ABSTRACT FROM AUTHOR]

Background: Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm.Method: This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26.Results: Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427-0.903, P 0.013) and higher oxygen saturation.Conclusion: Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted. [ABSTRACT FROM AUTHOR]

The Novel Coronavirus Disease 2019 (COVID-19) has swept the world and caused a global pandemic. SARS-CoV-2 seems to have originated from bats as their reservoir hosts over time. Similar to SARS-CoV, this new virus also exerts its action on the human angiotensin-converting enzyme 2. This action causes infections in cells and establishes an infectious disease, COVID-19. Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1β, IL-8, TNF-α, and other chemokines, such as G-CSF, IP10 and MCPl, which all develop and increase the inflammatory response. In cases of COVID-19, excessive inflammatory responses occur, and exaggerated proinflammatory cytokines and chemokines are detected in the serum, resulting in cytokine release syndrome or cytokine storm. This causes coagulation abnormalities, excessive oxidation developments, mitochondrial permeability transition, vital organ damage, immune system failure and eventually progresses to disseminated intravascular coagulation and multiple organ failure. Additionally, the excessive inflammatory responses also cause mitochondrial dysfunction due to progressive and persistent stress. This damages cells and mitochondria, leaving products containing mitochondrial DNA and cell debris involved in the excessive chronic inflammation as damage-associated molecular patterns. Thus, the respiratory infection progressively leads to disseminated intravascular coagulation from acute respiratory distress syndrome, including vascular endothelial cell damage and coagulation-fibrinolysis system disorders. This condition causes central nervous system disorders, renal failure, liver failure and, finally, multiple organ failure. Regarding treatment for COVID-19, the following are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. First, administering of favipiravir to suppress SARS-CoV-2 and nafamostat to inhibit ACE2 function should be considered. Second, anti-rheumatic drugs (monoclonal antibodies), which act on the leading cytokines (IL-1β, IL-6) and/or cytokine receptors such as tocilizumab, should be administered as well. Finally, melatonin may also have supportive effects for cytokine release syndrome, resulting in mitochondrial function improvement. This paper will further explore these subjects with reports mostly from China and Europe. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 first emerged in China during late 2019 and rapidly spread all over the world. Alterations in the inflammatory cytokines pathway represent a strong signature during SARS-COV-2 infection and correlate with poor prognosis and severity of the illness. The hyper-activation of the immune system results in an acute severe systemic inflammatory response named cytokine release syndrome (CRS). No effective prophylactic or post-exposure treatments are available, although some anti-inflammatory compounds are currently in clinical trials. Studies of plant extracts and natural compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation. The aim of this manuscript is to review the published background on the possible effectiveness of polyphenols to fight SARS-COV-2 infection, contributing to the reduction of inflammation. Here, some of the anti-inflammatory therapies are discussed and although great progress has been made though this year, there is no proven cytokine blocking agents for COVID currently used in clinical practice. In this regard, bioactive phytochemicals such as polyphenols may become promising tools to be used as adjuvants in the treatment of SARS-CoV-2 infection. Such nutrients, with anti-inflammatory and antioxidant properties, associated to classical anti-inflammatory drugs, could help in reducing the inflammation in patients with COVID-19. [ABSTRACT FROM AUTHOR]

Background: In December 2019, the novel coronavirus disease 2019 (COVID-19) emerged in Wuhan, Hubei Province, China. It rapidly spread and many cases were identified in multiple countries, posing a global health problem. Here, we report the first patient cured of COVID-19 infection in Changsha, China, and the symptoms, diagnosis, treatment, and management of this patient are all described in this report.Case Presentation: A 57-year-old woman developed cough and fever after returning to Changsha from Wuhan on January 9, 2020. She tested positive for COVID-19 infection, a diagnosis which was supported by chest CT. The patient was treated with lopinavir and ritonavir tablets and interferon alfa-2b injection. A low dose of glucocorticoids was used for a short period to control bilateral lung immune response, and this patient avoided being crushed by cytokine storms that might have occurred. The clinical condition of this patient improved, and a COVID-19 assay conducted on January 25, 2020 generated negative results. This patient recovered and was discharged on January 30, 2020.Conclusions: Currently, there are numerous reports on COVID-19 infections focusing on the disease's epidemiological and clinical characteristics. This case describes the symptoms, diagnosis, treatment, and management of a patient cured of COVID-19 infection, which may serve as reference for future cases, while further studies are needed. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a prominent pandemic disease that emerged in China and hurriedly stretched worldwide. There are many reports on COVID-19 associated with the amplified incidence of thrombotic events. In this review, we focused on COVID-19 coupled with the coagulopathy contributes to severe outcome inclusive of comorbidities such as venous thromboembolism, stroke, diabetes, lung, heart attack, AKI, and liver injury. Initially, the COVID-19 patient associated coagulation disorders show an elevated level of the D-dimer, fibrinogen, and less lymphocyte count such as lymphopenia. COVID-19 associated with the Kawasaki disease has acute vasculitis in childhood which further affects the vessels found all over the body. COVID-19 linked with the thrombotic microangiopathy triggers the multiple vasculitis along with the arterioles thrombosis, medium, large venous and arterial vessels mediates the disseminated intravascular coagulation (DIC). SARS-Co-V-2 patients have reduced primary platelet production, increased destruction of the platelet, decreased circulating platelet leads to the condition of increased thrombocytopenia which contributes to the coagulation disorder. Endothelial dysfunction plays an important role in the coagulation disorders via increased generation of the thrombin and stops fibrinolysis further leads to hypercoagulopathy. Along with that endothelial dysfunction activates the complement system pathways and contributes to the acute and chronic inflammation via cytokine storm with the production of the cytokines and chemokines, coagulation in different organs such as lung, brain, liver, heart, kidney and further leads to multi-organ failure. Unlabelled Image [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage. Discussion: We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Important cytokines involved in this phase are interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. This is typically followed by a recovery phase with production of antibodies against the virus. We summarize published data regarding virus-host interactions, key immunological mechanisms responsible for virus-associated CRS, and potential opportunities for therapeutic interventions. Conclusion: Evidence regarding SARS-CoV-2 epidemiology and pathogenesis is rapidly evolving. A better understanding of the pathophysiology and immune system dysregulation associated with CRS and acute respiratory distress syndrome in severe COVID-19 is imperative to identify novel drug targets and other therapeutic interventions. [ABSTRACT FROM AUTHOR]

• Cytokine storm is a key factor in the rapid deterioration of COVID-19. • Baricitinib could interrupt the passage of SARS-CoV-2 into the cells and treat cytokine storm. • The key points of pharmaceutical care have been elaborated in this article. In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1–2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19. [ABSTRACT FROM AUTHOR]

• As of June 2020, there is no approved medication therapy for COVID-19. • Past therapeutic data on SARS-CoV and MERS-CoV have inspired the search for potential cures in developed pharmacotherapies. • China's National Health Commission has issued the first COVID-19 management guide with several therapy suggestions. • The major therapeutics are evaluated in this review. • More well-designed clinical trials are needed to study the clinical efficacy of these agents. Currently, there is no approved therapy for coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) therefore endorses supportive care only. However, frontline clinicians and researchers have been experimenting with several virus-based and host-based therapeutics since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China. China's National Health Commission has issued the first COVID-19 treatment guidelines with therapy suggestions, which has inspired clinical studies worldwide. This review evaluates the major therapeutics. Key evidence from in vitro research, animal models and clinical research in emerging coronaviruses is examined. The antiviral therapies remdesivir, lopinavir/ritonavir and umifenovir, if considered, should be initiated before the peak of viral replication for an optimal outcome. Ribavirin may be beneficial as an add-on therapy but is ineffective as monotherapy. Corticosteroid use should be limited to specific co-morbidities. Intravenous immunoglobulin (IVIg) is not recommended owing to lack of data in COVID-19. The traditional Chinese medicine Xuebijing may benefit patients with complications of bacterial pneumonia or sepsis. The efficacy of interferon is unclear owing to conflicting outcomes in coronavirus studies. Chloroquine and hydroxychloroquine have shown in vitro inhibition of SARS-CoV-2, but studies on their clinical efficacy and whether the benefits outweigh the risk of dysrhythmias remain inconclusive. For patients who develop cytokine release syndrome, interleukin-6 inhibitors may be beneficial. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 is a novel strain, causing a global pandemic since the end of 2019. The majority of patients showed nonspecific symptoms such as fever, dry cough, and fatigue. Most patients have a good prognosis while some with severe conditions could rapidly progress to acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and even die. The exacerbation of the patient's condition may be due to a cytokine storm in the body. Effective targeted therapies including antiviral and immunization are urgently needed. Although many clinical trials are already underway and the majority of patients have received antiviral therapy based on medication experience with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and preliminary results from some clinical trials, there are no antiviral drugs proven to be effective currently. We summarize the current therapeutic medicines used in the clinic, hope to be able to provide some implications for clinical medication. [ABSTRACT FROM AUTHOR]

The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1β, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1β-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors. • COVID-19 induces both impairment and hyperactivation of the immune system. • Early viral clearance by type-I IFN is a key to preventing further viral replication, T cell exhaustion, and cytokine storm. • Timely administration of treatments may reduce viral load and avoid hyperinflammation. [ABSTRACT FROM AUTHOR]

On 7 January 2020, researchers isolated and sequenced in China from patients with severe pneumonitis a novel coronavirus, then called SARS-CoV-2, which rapidly spread worldwide, becoming a global health emergency. Typical manifestations consist of flu-like symptoms such as fever, cough, fatigue, and dyspnea. However, in about 20% of patients, the infection progresses to severe interstitial pneumonia and can induce an uncontrolled host-immune response, leading to a life-threatening condition called cytokine release syndrome (CRS). CRS represents an emergency scenario of a frequent challenge, which is the complex and interwoven link between infections and autoimmunity. Indeed, treatment of CRS involves the use of both antivirals to control the underlying infection and immunosuppressive agents to dampen the aberrant pro-inflammatory response of the host. Several trials, evaluating the safety and effectiveness of immunosuppressants commonly used in rheumatic diseases, are ongoing in patients with COVID-19 and CRS, some of which are achieving promising results. However, such a use should follow a multidisciplinary approach, be accompanied by close monitoring, be tailored to patient's clinical and serological features, and be initiated at the right time to reach the best results. Autoimmune patients receiving immunosuppressants could be prone to SARS-CoV-2 infections; however, suspension of the ongoing therapy is contraindicated to avoid disease flares and a consequent increase in the infection risk. [ABSTRACT FROM AUTHOR]

The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients. [ABSTRACT FROM AUTHOR]