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Background We examined effects of single-nucleotide variants (SNVs) of IL1RN , the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. Results Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P =.0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P =.052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P =.030). Conclusions The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T-cell (CAR-T) immunotherapy, a novel approach for treating blood cancer, is associated with the production of cytokine release syndrome (CRS), which poses significant safety concerns for patients. Currently, there is limited knowledge regarding CRS-related cytokines and the intricate relationship between cytokines and cells. Therefore, it is imperative to explore a reliable and efficient computational method to identify cytokines associated with CRS. In this study, we propose Meta-DHGNN, a directed and heterogeneous graph neural network analysis method based on meta-learning. The proposed method integrates both directed and heterogeneous algorithms, while the meta-learning module effectively addresses the issue of limited data availability. This approach enables comprehensive analysis of the cytokine network and accurate prediction of CRS-related cytokines. Firstly, to tackle the challenge posed by small datasets, a pre-training phase is conducted using the meta-learning module. Consequently, the directed algorithm constructs an adjacency matrix that accurately captures potential relationships in a more realistic manner. Ultimately, the heterogeneous algorithm employs meta-photographs and multi-head attention mechanisms to enhance the realism and accuracy of predicting cytokine information associated with positive labels. Our experimental verification on the dataset demonstrates that Meta-DHGNN achieves favorable outcomes. Furthermore, based on the predicted results, we have explored the multifaceted formation mechanism of CRS in CAR-T therapy from various perspectives and identified several cytokines, such as IFNG (IFN-γ), IFNA1, IFNB1, IFNA13, IFNA2, IFNAR1, IFNAR2, IFNGR1 and IFNGR2 that have been relatively overlooked in previous studies but potentially play pivotal roles. The significance of Meta-DHGNN lies in its ability to analyze directed and heterogeneous networks in biology effectively while also facilitating CRS risk prediction in CAR-T therapy. [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) occurs in 30% of patients infused with chimeric antigen receptor (CAR) T-cells. The purpose of this study was to identify risk factors and long-term outcomes after AKI in patients who received CAR T-cell therapy. Methods Medical records of 115 adult patients with R/R hematological malignancies treated with CD19-targeted CAR T-cells at Vall d'Hebron University Hospital between July 2018 and May 2021. Baseline demographic data including age, gender, ethnicity, body mass index (BMI), and co-morbidities, as well as the type of hematological neoplasia and prior lines of therapy were collected. Laboratory parameters including serum creatinine and whole blood hemoglobin were retrospectively reviewed and values were gathered for days +1, +7, +14, +21, and +28 post-infusion. Results A total of 24/115 (21%) patients developed AKI related to CAR T-cell therapy; 6/24 with AKI over chronic kidney disease (CKD). Two patients had AKI in the context of lymphodepleting (LD) chemotherapy and the other 22 after CAR T-cell infusion, starting at day+1 in 3 patients, day+7 in 13 patients, day +14 in 1 patient, day+21 in 2 patients, and day+28 in 3 patients. Renal function was recovered in 19/24 (79%) patients within the first month after infusion. Male gender, CKD, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with AKI. Male gender, CKD, ICANS grade ≥3 and CRS grade ≥2 were identified as independent risk factors for AKI on multivariable analysis. In terms of the most frequent CAR T-cell related complications, CRS was observed in 95 (82%) patients and ICANS in 33 (29%) patients. Steroids were required in 34 (30%) patients and tocilizumab in 37 (32%) patients. Six (5%) patients were admitted to the intensive care unit (1 for septic shock, 4 for CRS grade ≥2 associated to ICANS grade ≥2, and 1 for CRS grade ≥3). A total of 5 (4.4%) patients died in the first 30 days after CAR T-cell infusion for reasons other than disease progression, including 4 cases of infectious complications and 1 of heart failure. Conclusion Our results suggest that AKI is a frequent but mild adverse event, with fast recovery in most patients. [ABSTRACT FROM AUTHOR]

Background Intestinal microbiome contributes to the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GvHD) and loss of microbiome diversity influences the outcome of patients after allogeneic stem cell transplantation (SCT). Systemic broad-spectrum antibiotics have been identified as a major cause of early intestinal dysbiosis. Methods In 2017, our transplant unit at the university hospital in Regensburg changed the antibiotic strategy from a permissive way with initiation of antibiotics in all patients with neutropenic fever independent of the underlying cause and risk to a restrictive use in cases with high likelihood of cytokine release syndrome (eg, after anti-thymocyte globulin [ATG] therapy). We analyzed clinical data and microbiome parameters obtained 7 days after allogeneic SCT from 188 patients with ATG therapy transplanted in 2015/2016 (permissive cohort, n = 101) and 2918/2019 (restrictive cohort, n = 87). Results Restrictive antibiotic treatment postponed the beginning of antibiotic administration from 1.4 ± 7.6 days prior to 1.7 ± 5.5 days after SCT (P =.01) and significantly reduced the duration of antibiotic administration by 5.8 days (P <.001) without increase in infectious complications. Furthermore, we observed beneficial effects of the restrictive strategy compared with the permissive way on microbiome diversity (urinary 3-indoxylsulfate, P =.01; Shannon and Simpson indices, P <.001) and species abundance 7 days post-transplant as well as a positive trend toward a reduced incidence of severe GI GvHD (P =.1). Conclusions Our data indicate that microbiota protection can be achieved by a more careful selection of neutropenic patients qualifying for antibiotic treatment during allogeneic SCT without increased risk of infectious complications. [ABSTRACT FROM AUTHOR]

The article provides information on glofitamab-gxbm, an antineoplastic agent. Glofitamab-gxbm is used to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma. Also mentioned are its dosage and administration, warnings and precautions, and drug interactions. An advice to patients receiving glofitamab-gxmb is also included.

Motivation The reconstruction of small key regulatory networks that explain the differences in the development of cell (sub)types from single-cell RNA sequencing is a yet unresolved computational problem. Results To this end, we have developed SCANet, an all-in-one package for single-cell profiling that covers the whole differential mechanotyping workflow, from inference of trait/cell-type-specific gene co-expression modules, driver gene detection, and transcriptional gene regulatory network reconstruction to mechanistic drug repurposing candidate prediction. To illustrate the power of SCANet, we examined data from two studies. First, we identify the drivers of the mechanotype of a cytokine storm associated with increased mortality in patients with acute respiratory illness. Secondly, we find 20 drugs for eight potential pharmacological targets in cellular driver mechanisms in the intestinal stem cells of obese mice. Availability and implementation SCANet is a free, open-source, and user-friendly Python package that can be seamlessly integrated into single-cell-based systems medicine research and mechanistic drug discovery. [ABSTRACT FROM AUTHOR]

Due to the aggravation of bacterial drug resistance and the lag in the development of new antibiotics, it is crucial to develop novel therapeutic regimens for bacterial infectious diseases. Currently, immunotherapy is a promising regimen for the treatment of infectious diseases. Mucosal-associated invariant T (MAIT) cells, a subpopulation of innate-like T cells, are abundant in humans and can mount a rapid immune response to pathogens, thus becoming a potential target of immunotherapy for infectious diseases. At the site of infection, activated MAIT cells perform complex biological functions by secreting a variety of cytokines and cytotoxic substances. Many studies have shown that MAIT cells have immunoprotective effects because they can bridge innate and adaptive immune responses, leading to bacterial clearance, tissue repair, and homeostasis maintenance. MAIT cells also participate in cytokine storm generation, tissue fibrosis, and cancer progression, indicating that they play a role in immunopathology. In this article, we review recent studies of MAIT cells, discuss their dual roles in bacterial infectious diseases and provide some promising MAIT cell-targeting strategies for the treatment of bacterial infectious diseases. MAIT cells can be activated in a TCR-dependent manner and/or cytokine-dependent manner. Upon activation, MAIT cells may play a protective role or pathological role in bacterial infections. Therefore, clarifying the functions of MAIT cells in bacterial diseases is a crucial step for the application of MAIT cell-targeting immunotherapies in the clinic. [ABSTRACT FROM AUTHOR]

This article discusses the cutaneous adverse effects induced by tebentafusp, a recently approved immunotherapy agent, in patients with metastatic uveal melanoma. The study presents a case series of six patients who experienced cutaneous adverse reactions after receiving tebentafusp treatment. The most common reaction was pruritus, which was well-controlled with antihistamines in some patients but required more extensive treatment regimens in others. Severe reactions were managed with high-potency steroid wet wraps and aprepitant. The article emphasizes the need for further research on the range of adverse cutaneous reactions to tebentafusp and highlights the importance of recognizing and treating these effects. [Extracted from the article]

Donor cell leukaemia (DCL) is a complication of haematopoietic stem cell transplantation where donated cells become malignant within the patient's bone marrow. As DCL predominates as acute myeloid leukaemia, we hypothesized that the cytokine storm following chemotherapy played a role in promoting and supporting leukaemogenesis. Cytokines have also been implicated in genotoxicity; thus, we explored a cell line model of the human bone marrow (BM) to secrete myeloid cytokines following drug treatment and their potential to induce micronuclei. HS-5 human stromal cells were exposed to mitoxantrone (MTX) and chlorambucil (CHL) and, for the first time, were profiled for 80 cytokines using an array. Fifty-four cytokines were detected in untreated cells, of which 24 were upregulated and 10 were downregulated by both drugs. FGF-7 was the lowest cytokine to be detected in both untreated and treated cells. Eleven cytokines not detected at baseline were detected following drug exposure. TNFα, IL6, GM-CSF, G-CSF, and TGFβ1 were selected for micronuclei induction. TK6 cells were exposed to these cytokines in isolation and in paired combinations. Only TNFα and TGFβ1 induced micronuclei at healthy concentrations, but all five cytokines induced micronuclei at storm levels, which was further increased when combined in pairs. Of particular concern was that some combinations induced micronuclei at levels above the mitomycin C positive control; however, most combinations were less than the sum of micronuclei induced following exposure to each cytokine in isolation. These data infer a possible role for cytokines through chemotherapy-induced cytokine storm, in the instigation and support of leukaemogenesis in the BM, and implicate the need to evaluate individuals for variability in cytokine secretion as a potential risk factor for complications such as DCL. [ABSTRACT FROM AUTHOR]

In the current mpox outbreak, infections are usually self-limited. We describe 3 patients with uncontrolled HIV and mpox infections lasting months, causing debilitating lesions, complications, and death, despite initiating anti-mpox and antiretroviral therapy. Delayed treatment of mpox with antiviral agents may contribute to poor outcomes in severely immunocompromised patients. [ABSTRACT FROM AUTHOR]

Idiopathic multicentric Castleman disease (iMCD) is an infrequent and life-threatening disorder characterized by systemic inflammatory symptoms, generalized lymphadenopathy, polyclonal lymphocyte proliferation and organ dysfunction caused by a hyperinflammatory state. It accounts for one-third to one-half of all multicentric Castleman disease (MCD) cases. iMCD is often associated with autoimmune manifestations that may precede the iMCD diagnosis, be identified at the same time or follow it. In addition, iMCD may also coincide with a number of autoimmune diseases (such as psoriasis or myasthenia gravis) or autoinflammatory diseases (such as familial Mediterranean fever). Moreover, diverse inflammatory disorders, such as rheumatoid arthritis, systemic lupus erythematosus, adult-onset Still disease, systemic juvenile idiopathic arthritis, immunoglobulin (IgG4) related disease, or the recently described VEXAS syndrome, can present clinical features or lymphadenopathy with histopathological 'Castleman-like' findings compatible with those of iMCD. Given the iMCD clinical heterogeneity and the overlap with other autoimmune or autoinflammatory disorders, iMCD diagnosis can be challenging. In this review, we explore the overlap between iMCD and inflammatory diseases and provide practical guidance on iMCD diagnosis in order to avoid misdiagnosis and confusion with other autoimmune or autoinflammatory conditions. [ABSTRACT FROM AUTHOR]

Background Staphylococcus aureus co-infection is seldom reported in children with severe dengue. Methodology In this retrospective study, we reported five children with severe dengue and S. aureus  co-infection admitted to pediatric intensive care unit (PICU) during July–December 2021. Results All children had prolonged fever, persistence of bilateral pleural effusion beyond the critical phase, thrombocytopenia and raised inflammatory markers [C-reactive protein (CRP) and procalcitonin]. S. aureus  was isolated from pleural fluid (n  = 2, 40%), blood (n  = 2, 40%) and endotracheal aspirate (n  = 1, 20%). Four children (80%) grew methicillin-sensitive S. aureus , while 1 (20%) had methicillin-resistant S. aureus. Two children (40%) had septic thromboemboli in skin, and 1 (20%) had limb cellulitis. One child required anterior thoracotomy, pericardiectomy and bilateral pleural decortication, while all other children required intercostal chest tube drainage. All children required prolonged targeted antibiotics, invasive mechanical ventilation and had prolong stay in PICU and all of them survived. Conclusion In children with severe dengue, persistence of fever, persistence of pleural effusion beyond critical phase and raised CRP and procalcitonin should raise suspicion of bacterial/ S. aureus co-infection. [ABSTRACT FROM AUTHOR]

Objectives To multidimensionally characterize macrophage activation syndrome (MAS) complicating adult-onset Still's disease (AOSD) considering cytokine profile, inflammatory markers and multi-visceral involvement of the disease. To perform a high-dimensional phenotypic analysis of circulating immune cells in AOSD patients with and without MAS. To assess interferon (IFN)-related pathways in AOSD synovial tissues by a bulky RNA sequencing. Methods Clinical and biologic data were collected and compared in AOSD patients with and without MAS. Sera biomolecules were analysed by Luminex multiplexing technology. Mass cytometry (CyTOF) was used to characterize circulating immune cells. A bulky RNA sequencing was performed in AOSD synovial tissues. Results Forty consecutive AOSD patients were assessed, 14 complicated with MAS. Paralleling with increases of systemic score and ferritin, MAS patients showed higher levels of IL-1α, IL-1β, IL-1Ra, IL-2Ra, IL-6, IL-10, IL-17A, IFN-γ, G-CSF, MCP-1, MIP-1α and SCF. Combining the discriminatory ability of these data in identifying MAS, the best model was composed by systemic score, ferritin, IFN-γ and IL-10. By CyTOF analysis, MAS patients showed an increase of circulating 'classical monocytes' and a reduction of total NK cells. Our assessment showed 3477 IFN-related genes (IRGs) were differently expressed in AOSD synovial tissues. Conclusions A multidimensional characterization of AOSD patients suggested that IFN-γ, IL-10, ferritin and systemic score discriminated the occurrence of cytokine storm syndrome associated with MAS. The inflammatory milieu of AOSD and MAS may be related to a signature of circulating immune cells. Finally, our results about IRGs reinforced the role of IFN-γ in these patients. [ABSTRACT FROM AUTHOR]

The article presents a case study which characterized the functional and metabolic outcomes of an activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation in a patient affected by Langerhans-related histiocytosis. Topics include case of a patient with articular, pituitary and skin involvement, comparison between the supernatant of tissue lesions and tissue culture medium, and clinical effectiveness MAPK pathway inhibition with selective MEK inhibitors in histiocytosis patients.

Objective To evaluate upstream and downstream regulators leading to macrophage activation and subsequent cytokine storm in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-associated interstitial lung disease (ILD). Methods We conducted an integrated miRNA-mRNA association analysis using circulating monocytes from 3 patients with anti-MDA5-associated ILD and 3 healthy controls and identified disease pathways and a regulator effect network by Ingenuity Pathway Analysis (IPA). The expression of relevant genes and proteins was verified using an independent validation cohort, including 6 patients with anti-MDA5-associated ILD, 5 with anti-aminoacyl tRNA synthetase antibody-associated ILD, and 6 healthy controls. Results IPA identified 26 matched pairs of downregulated miRNA and upregulated mRNAs and revealed that canonical pathways mediated by type I IFN signalling and C-C motif ligand 2 (CCL2) were responsible for the pathogenic process (P < 0.05 for all pathways). The regulatory network model identified IFN-β; Toll-like receptors 3, 7, and 9; and PU.1 as upstream regulators, while the downstream effect of this network converged at the inhibition of viral infection. mRNA and protein expression analysis using validation cohort showed a trend towards the increased expression of relevant molecules identified by IPA in patients with anti-MDA5-associated ILD compared with those with anti-aminoacyl tRNA synthetase antibody-associated ILD or healthy controls. The expression of all relevant genes in monocytes and serum levels of CCL2 and IFN-β declined after treatment in survivors with anti-MDA5-associated ILD. Conclusion An antiviral proinflammatory network orchestrated primarily by activated monocytes/macrophages might be responsible for cytokine storm in anti-MDA5-associated ILD. [ABSTRACT FROM AUTHOR]

The Seraph-100™ is a purification filter that blunts cytokine storm, providing a more favorable environment to establish immune homeostasis. We present a novel case of compassionate use of Seraph filter in a young, healthy active duty service member with heat injury-induced massive inflammatory response. The patient is a previously healthy 26-year-old male with altered mental status, tachycardia, fever to 40.3 °C, and hypotension after losing consciousness during a 4-mile run. He had a history of one heat injury in college and took no medications or supplements. Initial workup demonstrated hemoconcentration, leukocytosis, and hyperkalemia. He was intubated, received isotonic crystalloid fluid, and was admitted to the intensive care unit. The patient developed vasopressor-resistant shock and multiorgan failure with rhabdomyolysis requiring continuous renal replacement therapy. The addition of the Seraph resulted in improved hemodynamic stability, decreased inflammatory markers, and improved organ function. Approximately 1 week after the final Seraph treatment, the patient had an abrupt massive lower gastrointestinal bleed and was transitioned to comfort care by family. We present the novel use of Seraph in the setting of multiorgan failure and hyperinflammatory state due to heat injury. The patient's vasopressor refractory distributive shock was believed to be secondary to heat stroke-induced massive inflammatory response, leading to a trial of Seraph therapy. This case demonstrates that the Seraph filter has the potential to improve hemodynamic instability and reduce cytokine storm in nonsepsis patients. [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]

Background: Coronavirus disease 2019 (COVID-19) can progress to severe pneumonia with respiratory failure and is aggravated by the deregulation of the immune system causing an excessive inflammation including the cytokine storm.Methods: In this study, we report that severe acutely infected patients have high levels of both type-1 and type-2 cytokines.Results: Our results show abnormal cytokine levels upon T-cell stimulation, in a nonpolarized profile. Furthermore, our findings indicate that this hyperactive cytokine response is associated with a significantly increased frequency of late-differentiated T cells with particular phenotype of effector exhausted/senescent CD28-CD57+ cells. Of note, we demonstrated for the first time an increased frequency of CD3+CD4+CD28-CD57+ T cells with expression of programmed death 1, one of the hallmarks of T-cell exhaustion.Conclusions: These findings reveal that COVID-19 is associated with acute immunodeficiency, especially within the CD4+ T-cell compartment, and points to possible mechanisms of loss of clonal repertoire and susceptibility to viral relapse and reinfection events. [ABSTRACT FROM AUTHOR]

Background Recent findings indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune‐mediated mechanisms. Very few studies have fully investigated the cerebrospinal fluid (CSF) correlates of SARS-CoV-2 encephalitis. Methods Patients with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC), and healthy controls (HC) underwent an extended panel of CSF neuronal (neurofilament light chain [NfL], T-tau), glial (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], chitinase-3-like protein 1 [YKL-40]) and inflammatory biomarkers (interleukin [IL]-1β, IL-6, Il-8, tumor necrosis factor [TNF] α, CXCL-13, and β2-microglobulin). Results Thirteen COV-Enc, 21 ENC, and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-tau were abnormal only in severe cases. Conclusions SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2-related encephalitis. [ABSTRACT FROM AUTHOR]

Blockade of IL-6 function by an anti-IL-6 receptor (IL-6R) antibody (tocilizumab, trade name Actemra) has been shown to be effective for the treatment of chronic autoimmune inflammatory diseases including rheumatoid arthritis. Interestingly, treatment with tocilizumab has also been found to alleviate the cytokine storm induced by chimeric antigen receptor (CAR)-T-cell therapy. Patients with serious cases of coronavirus disease 2019 (COVID-19) exhibit cytokine release syndrome (CRS), which suggested that tocilizumab might be an effective therapeutic for serious cases of COVID-19. In the first part of this short review, the therapeutic effect of tocilizumab for the disease induced by IL-6 overproduction is described. CRS induced by CAR-T-cell therapy and COVID-19 is then discussed. [ABSTRACT FROM AUTHOR]

Motivation COVID-19 has several distinct clinical phases: a viral replication phase, an inflammatory phase and in some patients, a hyper-inflammatory phase. High mortality is associated with patients developing cytokine storm syndrome. Treatment of hyper-inflammation in these patients using existing approved therapies with proven safety profiles could address the immediate need to reduce mortality. Results We analyzed the changes in the gene expression, pathways and putative mechanisms induced by SARS-CoV2 in NHBE, and A549 cells, as well as COVID-19 lung versus their respective controls. We used these changes to identify FDA approved drugs that could be repurposed to help COVID-19 patients with severe symptoms related to hyper-inflammation. We identified methylprednisolone (MP) as a potential leading therapy. The results were then confirmed in five independent validation datasets including Vero E6 cells, lung and intestinal organoids, as well as additional patient lung sample versus their respective controls. Finally, the efficacy of MP was validated in an independent clinical study. Thirty-day all-cause mortality occurred at a significantly lower rate in the MP-treated group compared to control group (29.6% versus 16.6%, P  =   0.027). Clinical results confirmed the in silico prediction that MP could improve outcomes in severe cases of COVID-19. A low number needed to treat (NNT = 5) suggests MP may be more efficacious than dexamethasone or hydrocortisone. Availability and implementation iPathwayGuide is available at https://advaitabio.com/ipathwayguide/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Adult-onset Still's disease (AOSD) is a rare, but characteristic non-familial, multi-genic systemic auto-inflammatory disorder, characterized by high spiking fever, salmon-like evanescent skin rash, polyarthritis, sore throat, hyperferritinemia and leucocytosis. The hallmark of AOSD is a cytokine storm triggered by dysregulation of inflammation. Nowadays, with advances in anti-cytokine biologic agents, the treatment of AOSD is no longer limited to NSAIDs, glucocorticoids or conventional synthetic DMARDs. In this review, we focussed on the roles of these cytokines in the pathogenesis of AOSD and summarized the current and emerging biological therapy. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has spread rapidly throughout the globe. The spectrum of disease is broad but among hospitalized patients with COVID-19, respiratory failure from acute respiratory distress syndrome is the leading cause of mortality. There is an urgent need for an effective treatment. The current focus has been developing novel therapeutics, including antivirals, protease inhibitors, vaccines and targeting the overactive cytokine response with anti-cytokine therapy. The overproduction of early response proinflammatory cytokines results in what has been described as a "cytokine storm" is leading eventually to death when the cells fail to terminate the inflammatory response. Accumulating evidence shows that inflammatory cytokines induce selectin ligands that play a crucial role in the pathogenesis of inflammatory diseases by mediating leukocyte migration from the blood into the tissue. Thus, the selectins and selectin ligands represent a promising therapeutic target for the treatment of COVID-19. In this paper, potential pan-selectin inhibitors were identified employing a virtual screening using a docking procedure. For this purpose, the Asinex and ZINC databases of ligands, including approved drugs, biogenic compounds and glycomimetics, altogether 923,602 compounds, were screened against the P-, L- and E-selectin. At first, the experimentally confirmed inhibitors were docked into all three selectins' carbohydrate recognition domains to assess the suitability of the screening procedure. Finally, based on the evaluation of ligands binding, we propose 10 purchasable pan-selectin inhibitors to develop COVID-19 therapeutics. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic in Japan is not as disastrous as it is in other Western countries, possibly because of certain lifestyle factors. One such factor might be the seaweed-rich diet commonly consumed in Japan. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which binds to angiotensin-converting enzyme 2 (ACE2) on the cell surface and downregulates ACE2, likely elevating the ratio of angiotensin-converting enzyme (ACE) to ACE2. The overreaction of the immune system, combined with the cytokine storm and ACE dominance, is purported to cause the condition of COVID-19 patients to deteriorate rapidly. Dietary seaweeds contain numerous components, including ACE inhibitory peptides, soluble dietary fibers (eg, fucoidan, porphyran), omega-3 fatty acids, fucoxanthin, fucosterol, vitamins D3 and B12, and phlorotannins. These components exert antioxidant, anti-inflammatory, and antiviral effects directly as well as indirectly through prebiotic effects. It is possible that ACE inhibitory components could minimize the ACE dominance caused by SARS-CoV-2 infection. Thus, dietary seaweeds might confer protection against COVID-19 through multiple mechanisms. Overconsumption of seaweeds should be avoided, however, as seaweeds contain high levels of iodine. [ABSTRACT FROM AUTHOR]

Adoptive cell therapies are a group of cancer immunotherapies that involve the infusion of engineered immune cells targeting specific tumor antigens, with chimeric antigen receptor (CAR) T cells at the vanguard of this revolution in cancer therapy. Several CAR T-cell products have been approved for the treatment of leukemia and lymphoma and many more are currently undergoing evaluation in clinical trials for the treatment of other liquid and solid malignancies. Despite their remarkable effectiveness, as with other immunotherapies, CAR T cells are frequently associated with systemic and neurologic toxicity. There has been a major effort by many institutions to develop specific protocols to guide the management of treatment-associated toxicities (eg, cytokine release syndrome [CRS]). However, neurotoxic effects of CAR T-cell therapies are more difficult to evaluate and treat, not easily lending themselves to an algorithmic approach to diagnosis and management. Given the steadily expanding use of CAR T-cell therapies for various malignancies, it is of critical importance for neuro-oncologists to be familiar with the clinical presentation and management principles of CAR T-cell-associated neurotoxicity. Here, we present key principles for the evaluation and management of patients affected by CAR T-cell-associated neurotoxicity based on the most recent evidence. [ABSTRACT FROM AUTHOR]

Staphylococcal enterotoxin B (SEB), which is produced by the major human pathogen, Staphylococcus aureus, represents a powerful superantigenic toxin and is considered a bioweapon. However, the contribution of SEB to S. aureus pathogenesis has never been directly demonstrated with genetically defined mutants in clinically relevant strains. Many isolates of the predominant Asian community-associated methicillin-resistant S. aureus lineage sequence type (ST) 59 harbor seb, implying a significant role of SEB in the observed hypervirulence of this lineage. We created an isogenic seb mutant in a representative ST59 isolate and assessed its virulence potential in mouse infection models. We detected a significant contribution of seb to systemic ST59 infection that was associated with a cytokine storm. Our results directly demonstrate that seb contributes to S. aureus pathogenesis, suggesting the value of including SEB as a target in multipronged antistaphylococcal drug development strategies. Furthermore, they indicate that seb contributes to fatal exacerbation of community-associated methicillin-resistant S. aureus infection. [ABSTRACT FROM AUTHOR]

Some clusters of children with a multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. We describe the epidemiological and clinical features of children with MIS-C in Spain. MIS-C is a potentially severe condition that presents in children with recent SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) binds to the IL-6 receptor (IL-6R) subunit, related to autoimmune diseases and cytokine storm in COVID-19. In this study, we performed systematic evolution of ligands by exponential enrichment and identified a novel RNA aptamer. This RNA aptamer not only bound to IL-6R with a dissociation constant of 200 n  m , but also inhibited the interaction of IL-6R with IL-6. [ABSTRACT FROM AUTHOR]

Objective: Alterations in thyroid function tests (TFTs) have been recorded during SARS-CoV-2 infection as associated to either a destructive thyroiditis or a non-thyroidal illness. Methods: We studied 144 consecutive COVID-19 patients admitted to a single center in intensive or subintensive care units. Those with previous thyroid dysfunctions or taking interfering drugs were excluded. Differently from previous reports, TSH, FT3, FT4, thyroglobulin (Tg), anti-Tg autoantibodies (TgAb) were measured at baseline and every 3–7 days. C-reacting protein (CRP), cortisol and IL-6 were also assayed. Results: The majority of patients had a normal TSH at admission, usually with normal FT4 and FT3. Low TSH levels were found either at admission or during hospitalization in 39% of patients, associated with low FT3 in half of the cases. FT4 and Tg levels were normal, and TgAb-negative. TSH and FT3 were invariably restored at the time of discharge in survivors, whereas were permanently low in most deceased cases, but only FT3 levels were predictors of mortality. Cortisol, CRP and IL-6 levels were higher in patients with low TSH and FT3 levels. Conclusions: Almost half of our COVID-19 patients without interfering drugs had normal TFTs both at admission and during follow-up. In this series, the transient finding of low TSH with normal FT4 and low FT3 levels, inversely correlated with CRP, cortisol and IL-6 and associated with normal Tg levels, is likely due to the cytokine storm induced by SARS-Cov-2 with a direct or mediated impact on TSH secretion and deiodinase activity, and likely not to a destructive thyroiditis. [ABSTRACT FROM AUTHOR]

Objectives: Laboratory testing and the measurement of appropriate biomarkers play a critical role in managing patients with coronavirus disease 2019 (COVID-19), allowing for disease diagnosis, monitoring progression, prognostication, prediction of treatment response, and risk stratification. We sought to characterize these effects on a more detailed, mechanistic level.Methods: We reviewed the literature and identified a multitude of reports that describe the unique effects of this virus and its devastating consequences to multiple organ systems in COVID-19 patients.Results: There are specific alterations in biomarkers related to coagulation, depopulation of T-cell subtypes, the cytokine storm and inflammation, and kidney and cardiac dysfunction.Conclusions: Laboratory measurement of specific parameters and the use of appropriate prognostic, predictive, and monitoring biomarkers afford clinicians the ability to make informed medical decisions and guide therapy for patients afflicted with this dreaded disease. [ABSTRACT FROM AUTHOR]

Older adults are far more vulnerable to adverse health outcomes and mortality after contracting COVID-19. There are likely multiple age-related biological, clinical, and environmental reasons for this increased risk, all of which are exacerbated by underlying age-associated changes to the immune system as well as increased prevalence of chronic disease states in older adults. Innate immune system overactivity, termed the cytokine storm, appears to be critical in the development of the worst consequences of COVID-19 infection. Pathophysiology suggests that viral stimulation of the innate immune system, augmented by inflammatory signals sent from dying cells, ramps up into a poorly controlled outpouring of inflammatory mediators. Other aging-related changes in cells such as senescence as well as higher prevalence of chronic disease states also likely ramp up inflammatory signaling. This in turn drives downstream pathophysiological changes to pulmonary, cardiovascular, skeletal muscle, and brain tissues that drive many of the adverse health outcomes observed in older adults. This article provides an overview of the underlying etiologies of innate immune system activation and adaptive immune system dysregulation in older adults and how they potentiate the consequences of the COVID-19-related cytokine storm, and possible uses of this knowledge to develop better risk assessment and treatment monitoring strategies. [ABSTRACT FROM AUTHOR]

Emerging viral infections seriously threaten human health globally. Several challenges exist in identifying effective compounds against viral infections: (1) at the initial stage of a new virus outbreak, little information, except for its genome information, may be available; (2) although the identified compounds may be effective, they may be toxic in vivo and (3) cytokine release syndrome (CRS) triggered by viral infections is the primary cause of mortality. Currently, an integrative tool that takes all those aspects into consideration for identifying effective compounds to prevent viral infections is absent. In this study, we developed iDMer, as an integrative and mechanism-driven response system for addressing these challenges during the sudden virus outbreaks. iDMer comprises three mechanism-driven compound identification modules, that is, a virus-host interaction-oriented module, an autophagy-oriented module and a CRS-oriented module. As a one-stop integrative platform, iDMer incorporates compound toxicity evaluation and compound combination identification for virus treatment with clear mechanisms. iDMer was successfully tested on five viruses, including the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results indicated that, for all five tested viruses, compounds that were reported in the literature or experimentally validated for virus treatment were enriched at the top, demonstrating the generalized effectiveness of iDMer. Finally, we demonstrated that combinations of the individual modules successfully identified combinations of compounds effective for virus intervention with clear mechanisms. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of interleukin-6 inhibitors (IL-6i) in ameliorating coronavirus disease 2019 (COVID-19) remains uncertain.Methods: We analyzed data for patients aged ≥18 years admitted with a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test at 4 safety-net hospital systems with diverse populations and high rates of medical comorbidities in 3 US regions. We used inverse probability of treatment weighting via machine learning for confounding adjustment by demographics, comorbidities, and disease severity markers. We estimated the average treatment effect, the odds of IL-6i effect on in-hospital mortality from COVID-19, using a logistic marginal structural model.Results: Of 516 patients, 104 (20.1%) received IL-6i. Estimate of the average treatment effect adjusted for confounders suggested a 37% reduction in odds of in-hospital mortality in those who received IL-6i compared with those who did not, although the confidence interval included the null value of 1 (odds ratio = 0.63; 95% confidence interval, .29-1.38). A sensitivity analysis suggested that potential unmeasured confounding would require a minimum odds ratio of 2.55 to nullify our estimated IL-6i effect size.Conclusions: Despite low precision, our findings suggested a relatively large effect size of IL-6i in reducing the odds of COVID-19-related in-hospital mortality. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL; Leishmania donovani) cases produce interferon-γ and tumor necrosis factor in response to soluble leishmanial antigen (SLA) in whole-blood assays. Using transcriptional profiling, we demonstrate the impact of interleukin-10 (IL-10), a cytokine implicated in VL, on this response. SLA stimulation identified 28 differentially expressed genes (DEGs), 17/28 in a single network with TNF as hub. SLA plus anti-IL-10 produced 454 DEGs, 292 in a single network with TNF, IFNG, NFKBIA, IL6, and IL1B as hubs in concert with a remarkable chemokine/cytokine storm. Our data demonstrate the singular effect of IL-10 as a potent immune modulator in VL. [ABSTRACT FROM AUTHOR]

Background Coronavirus disease 2019 (COVID-19) is characterized by immune-mediated lung injury and complex alterations of the immune system, such as lymphopenia and cytokine storm, that have been associated with adverse outcomes underlining a fundamental role of host response in severe acute respiratory syndrome coronavirus 2 infection and the pathogenesis of the disease. Thymosin alpha 1 (Tα1) is one of the molecules used in the management of COVID-19, because it is known to restore the homeostasis of the immune system during infections and cancer. Methods In this study, we captured the interconnected biological processes regulated by Tα1 in CD8+ T cells under inflammatory conditions. Results Genes associated with cytokine signaling and production were upregulated in blood cells from patients with COVID-19, and the ex vivo treatment with Tα1-mitigated cytokine expression, and inhibited lymphocyte activation in a CD8+ T-cell subset specifically. Conclusion These data suggest the potential role of Tα1 in modulating the immune response homeostasis and the cytokine storm in vivo. [ABSTRACT FROM AUTHOR]

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a current pandemic worldwide. This virus can reach all organs and disturbs the immune system, leading to a cytokine storm in severe forms. We aimed to report cutaneous features among coronavirus disease 2019 (COVID-19) hospitalized patients. Methods We performed a cross-sectional study on 1 given day among all patients hospitalized in acute care for COVID-19 and included all patients with cutaneous features. Follow-up 48 hours later was obtained. Results Among 59 adult patients hospitalized on the day of the study in an infectious diseases ward for SARS-CoV-2 infection who were confirmed by molecular assay and/or radiological findings (computed tomography scan), 40 were included. Several cutaneous manifestations were found: macular exanthema (80%), face edema (32%), livedo (13%), urticarial rash (8%), purpura (5%), oral lichenoid lesions (33%), and conjunctivitis (18%). Cutaneous biopsy was performed in 17 patients. Histological findings showed mast cell hyperplasia (100%), superficial perivascular infiltrate of lymphocytes (94%), and superficial edema (47%) consistent with capillary leak. Conclusions Various dermatological signs can be encountered during COVID-19. A macular rash was the most frequent. All cutaneous features could be related to a vascular leak process. [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]

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]

Objectives: A subset of coronavirus disease 2019 (COVID-19) patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis (HLH) have not been reported. We studied the reticuloendothelial organs of 4 consecutive patients who died of COVID-19 and correlated with clinical and laboratory parameters to detect HLH.Methods: Autopsies were performed on 4 patients who died of COVID-19. Routine H&E staining and immunohistochemical staining for CD163 were performed to detect hemophagocytosis. Clinical and laboratory results from premortem blood samples were used to calculate H-scores.Results: All 4 cases demonstrated diffuse alveolar damage within the lungs. Three of the 4 cases had histologic evidence of hemophagocytosis within pulmonary lymph nodes. One case showed hemophagocytosis in the spleen but none showed hemophagocytosis in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis observed. One patient showed diagnostic features of HLH with an H-score of 217, while a second patient likely had HLH with a partial H-score of 145 due to a missing triglyceride level. The remaining 2 patients had H-scores of 131 and 96.Conclusions: This is the first report of severe acute respiratory syndrome coronavirus 2-associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies. [ABSTRACT FROM AUTHOR]

A 29-year-old female presented with fever, headache, and epigastric pain. Though her initial presentation was benign and nonspecific, she soon developed a full-blown cytokine storm with disseminated intravascular coagulation. She was diagnosed with hemophagocytosis secondary to Rickettsia conorii infection. A good outcome was achieved thanks to prompt diagnosis and proper treatment. [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]

Understanding mechanisms of the novel SARS‐CoV2 infection and progression can provide potential novel targets for prevention and/or treatment. This could be achieved via the inhibition of viral entry and/or replication, or by suppression of the immunologic response that is provoked by the infection (known as the cytokine storm). Probiotics are defined as 'live microorganisms that, when administered in adequate amounts, confer a health benefit on the host'. There is scarcity of evidence about the relationship between COVID‐19 and gut microbiota. So, whether or not these supplements can prevent or ameliorate COVID‐19‐associated symptoms is not fully understood. The aim of this study is to provide an indirect evidence about the utility of probiotics in combating COVID‐19 or its associated symptoms, through the review of its antiviral and anti‐inflammatory properties in vitro, animal models and human trials. Significance and Impact of the Study: The role of probiotics in alleviation of the novel COVID‐19 has not been established. This review provides an insight about the anti‐inflammatory, antiviral effects of probiotics in vitro, animal models and human. The latter can provide an indirect evidence and/or hypothesis‐driven approach to investigate the use of probiotics as adjunctive therapy in the prophylaxis and/or alleviation of COVID‐19 symptoms. [ABSTRACT FROM AUTHOR]

Background COVID-19 is an ongoing threat to society. Patients who develop the most severe forms of the disease have high mortality. The interleukin-6 inhibitor tocilizumab has the potential to improve outcomes in these patients by preventing the development of cytokine release storm. Aims To evaluate the outcomes of patients with severe COVID-19 disease treated with the interleukin-6 inhibitor tocilizumab. Methods We conducted a retrospective, case–control, single-center study in patients with severe to critical COVID-19 disease treated with tocilizumab. Disease severity was defined based on the amount of oxygen supplementation required. The primary endpoint was the overall mortality. Secondary endpoints were mortality in non-intubated patients and mortality in intubated patients. Results A total of 193 patients were included in the study. Ninety-six patients received tocilizumab, while 97 served as the control group. The mean age was 60 years. Patients over 65 years represented 43% of the population. More patients in the tocilizumab group reported fever, cough and shortness of breath (83%, 80% and 96% vs. 73%, 69% and 71%, respectively). There was a non-statistically significant lower mortality in the treatment group (52% vs. 62.1%, P  = 0.09). When excluding intubated patients, there was statistically significant lower mortality in patients treated with tocilizumab (6% vs. 27%, P  = 0.024). Bacteremia was more common in the control group (24% vs. 13%, P  = 0.43), while fungemia was similar for both (3% vs. 4%, P  = 0.72). Conclusion Our study showed a non-statistically significant lower mortality in patients with severe to critical COVID-19 disease who received tocilizumab. When intubated patients were excluded, the use of tocilizumab was associated with lower mortality. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a pandemic of unprecedented severity affecting millions of people around the world and causing several hundred thousands of deaths. The presentation of the disease ranges from asymptomatic manifestations through to acute respiratory distress syndrome with the necessity of mechanical ventilation. Cytokine storm and maladaptive responses to the viral spread in the body could be responsible for the severity of disease. Many patients develop acute kidney injury (AKI) during the course of their disease, especially in more severe cases. Many factors could cause kidney damage during infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is still unclear whether direct viral damage or the overexpression of cytokines and inflammatory factors are preeminent. According to autoptic studies, in most of the cases, AKI is due proximal tubular damage. However, cases of collapsing focal segmental glomerulosclerosis were reported as well in the absence of signs of direct viral infection of the kidney. Considering that severe hypoxia is a hallmark of severe SARS-CoV-2 infection, the involvement of the hypoxia-inducible factor (HIF) system is very likely, possibly influencing the inflammatory response and outcome in both the lungs and kidneys. Several bodies of evidence have shown a possible role of the HIF pathway during AKI in various kidney disease models. Similar observations were made in the setting of acute lung injury. In both organs, HIF activation by means of inhibition of the prolyl-hydroxylases domain (PHD) could be protective. Considering these promising experimental data, we hypothesize that PHD inhibitors could be considered as a possible new therapy against severe SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS) and Coronavirus Disease 2019 (COVID-19) are caused by three distinct coronaviruses belonging to the same genus. COVID-19 and its two predecessors share many important features in their clinical presentations, and in their propensity for progression to severe disease which is marked by high rates of morbidity and mortality. However, comparison of the three viral illnesses also reveals a number of specific differences in clinical manifestations and complications, which suggest variability in the disease process. This narrative review delineates the pulmonary, cardiac, renal, gastrointestinal, hepatic, neurological and hematologic complications associated with these three respiratory coronaviruses. It further describes the mechanisms of immune hyperactivation—particularly cytokine release syndrome—implicated in the multi-organ system injury seen in severe cases of MERS, SARS and COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Nicotine can robustly increase responding for conditioned reinforcers (CRs), stimuli that acquire reinforcing properties based on association with primary reinforcers. Menthol and licorice are tobacco flavoring agents also found in sweet foods (eg, candy and ice cream), making them putative CRs before they are consumed in tobacco. We sought to determine if intravenous self-administration (IVSA) of nicotine was enhanced by the inclusion of oral tobacco flavor CRs.Methods: Menthol (160 or 320 µM) or licorice root extract (0.1% or 1%) were established as CRs (paired with 20% sucrose) or "neutral" stimuli (paired with water) in separate groups. During subsequent IVSA tests, nicotine was delivered in conjunction with oral presentations of the CR.Results: In experiment 1, a menthol CR significantly shifted the peak nicotine dose from 15 µg/kg/infusion (Neutral group) to 3.25 µg/kg/infusion (CR group). In experiment 2, a menthol CR significantly increased operant licks for nicotine (3 µg/kg/infusion) relative to control groups. In experiment 3, both licorice and menthol CRs significantly increased operant licks for nicotine (7.5 µg/kg/infusion) relative to an "inactive" sipper. The licorice CR increased nicotine IVSA in proportion to the strength of the flavor, but both menthol concentrations increased nicotine IVSA to a similar extent.Conclusion: Tobacco flavor additives with conditioned reinforcing properties promote acquisition of nicotine self-administration at low unit doses and may have robust impact on tobacco consumption when nicotine yield is low.Implications: Tobacco flavor additives are found in rewarding foods (eg, ice cream) and gain palatability based on associations with primary rewards (eg, sugar) making them "conditioned reinforcers." Nicotine increases the motivation for flavor conditioned reinforcers and the present studies show that tobacco flavor additives can interact with nicotine to promote more nicotine self-administration. The interaction between flavors additives and nicotine may promote nicotine exposure and subsequently dependence. [ABSTRACT FROM AUTHOR]

Summary: Cytokines have been extensively studied in coeliac disease, but cytokine release related to exposure to gluten and associated symptoms has only recently been described. Prominent, early elevations in serum interleukin (IL)‐2 after gluten support a central role for T cell activation in the clinical reactions to gluten in coeliac disease. The aim of this study was to establish a quantitative hierarchy of serum cytokines and their relation to symptoms in patients with coeliac disease during gluten‐mediated cytokine release reactions. Sera were analyzed from coeliac disease patients on a gluten free‐diet (n = 25) and from a parallel cohort of healthy volunteers (n = 25) who underwent an unmasked gluten challenge. Sera were collected at baseline and 2, 4 and 6 h after consuming 10 g vital wheat gluten flour; 187 cytokines were assessed. Confirmatory analyses were performed by high‐sensitivity electrochemiluminescence immunoassay. Cytokine elevations were correlated with symptoms. Cytokine release following gluten challenge in coeliac disease patients included significant elevations of IL‐2, chemokine (C‐C motif) ligand 20 (CCL20), IL‐6, chemokine (C‐X‐C motif) ligand (CXCL)9, CXCL8, interferon (IFN)‐γ, IL‐10, IL‐22, IL‐17A, tumour necrosis factor (TNF)‐α, CCL2 and amphiregulin. IL‐2 and IL‐17A were earliest to rise. Peak levels of cytokines were generally at 4 h. IL‐2 increased most (median 57‐fold), then CCL20 (median 10‐fold). Cytokine changes were strongly correlated with one another, and the most severely symptomatic patients had the highest elevations. Early elevations of IL‐2, IL‐17A, IL‐22 and IFN‐γ after gluten in patients with coeliac disease implicates rapidly activated T cells as their probable source. Cytokine release after gluten could aid in monitoring experimental treatments and support diagnosis. [ABSTRACT FROM AUTHOR]

Background Chimeric antigen receptor (CAR)–modified T cells that target the CD19 antigen present a novel promising therapy for the treatment of relapsed B-cell acute lymphoblastic leukemia (B-ALL). Although cytokine release syndrome (CRS) and neurotoxicity have emerged as predominant noninfectious complications of CD19 CAR T-cell therapy, infections associated with this treatment modality have not been well documented. Methods We analyzed infectious complications that followed CD19 CAR T-cell therapy in 53 adult patients with relapsed B-ALL enrolled in a phase I clinical trial at Memorial Sloan Kettering Cancer Center (NCT01044069). Results Overall, 22 patients (42%) experienced 26 infections (17 bacterial, 4 fungal, and 5 viral) within the first 30 days of CAR T-cell infusion. In 10 of 32 (31%) patients in whom complete remission was achieved, 15 infections developed between days 31 and 180; the majority of these late infections were due to respiratory viruses. In general, bacterial, fungal, and viral infections were detected at a median of 18, 23, and 48 days, respectively, after CAR T-cell infusion. CRS grade 3 or higher was independently associated with increased risk of subsequent infection (adjusted hazard ratio [HR], 2.67; P =.05) and in particular with bloodstream infection (adjusted HR, 19.97; P <.001). Three of 53 patients (6%) died of an infection-related cause. Conclusions Infections in adult patients with relapsed B-ALL are common after CD19 CAR T-cell therapy. Understanding the infectious complications that are temporally coincident with CD19 CAR T-cell therapy is critical for developing effective prophylactic and other supportive care measures to improve clinical outcomes. Clinical Trials Registration NCT01044069. [ABSTRACT FROM AUTHOR]

Cancer treatments, particularly immunotherapies, are known to affect inflammatory responses, and it is yet unknown how this may affect the disease course of COVID-19 in those receiving active cancer treatment. It is worth noting that patients who had received an allogeneic stem cell transplant or chimeric antigen receptor T-cell therapy at any time in the past were eligible for our study; our intent was to capture a wide range of patients with ongoing immune effects of treatment. In the transplant treatment category, only 13% had received chimeric antigen receptor T-cell therapy, and of those, the majority received treatment treated more than 3 months prior to their diagnosis of COVID-19, making it unlikely that concurrent cytokine release syndrome was present. [Extracted from the article]