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Cytokine storm

Yini Wang, Zhao Wang
PURPOSE OF REVIEW: Hemophagocytic lymphohistiocytosis (HLH) is a condition of uncontrolled immune activation with a high mortality rate. The recommended therapeutic guideline for HLH was published by the Histiocyte Society in 1994 and revised in 2004, which greatly improved the survival in patients with HLH. However, HLH is still a refractory disease for which the search for novel treatments continues. This article overviewed recent advances in treatment of HLH. RECENT FINDINGS: Current practices in treatment extend from chemo-immunotherapy to some new cytokine-targeting biologicals, which are more effective to eliminate pathologically activated T cells and resist exaggerated cytokine storm...
October 15, 2016: Current Opinion in Hematology
Semmannan Kalaiyarasu, Manoj Kumar, Dhanapal Senthil Kumar, Sandeep Bhatia, Sandeep Kumar Dash, Sushant Bhat, Rohit K Khetan, Shanmugasundaram Nagarajan
One of the major causes of death in highly pathogenic avian influenza virus (HPAIV) infection in chicken is due to acute induction of pro-inflammatory cytokine (cytokine storm) which leads to severe pathology and acute mortality. Dendritic cells and macrophages of respiratory tract are the major antigen presenting cells (APCs) getting exposed to mucosal pathogens. We hypothesized that chicken dendritic cells might be a major target for H5N1 HPAIV for induction of cytokine dysregulation. Infection of chMoDCs with H5N1 HPAIV produced high titers of progeny virus with more rounding and cytotoxicity than H9N2 LPAIV...
October 12, 2016: Microbiology and Immunology
I L Indalao, T Sawabuchi, E Takahashi, H Kido
Severe influenza is characterized by a cytokine storm, and the influenza virus-cytokine-trypsin cycle is one of the important mechanisms of viral multiplication and multiple organ failure. The aim of this study was to define the key cytokine(s) responsible for trypsin upregulation. Mice were infected with influenza virus strain A/Puerto Rico/8/34 (H1N1) or treated individually or with a combination of interleukin-1β, interleukin-6, and tumor necrosis factor α. The levels of these cytokines and trypsin in the lungs were monitored...
October 6, 2016: Archives of Virology
Revital Levy, Ziv Rotfogel, Dalia Hillman, Andrey Popugailo, Gila Arad, Emmanuelle Supper, Farhat Osman, Raymond Kaempfer
Full T-cell activation requires interaction between the costimulatory receptors B7-2 and CD28. By binding CD28, bacterial superantigens elicit harmful inflammatory cytokine overexpression through an unknown mechanism. We show that, by engaging not only CD28 but also its coligand B7-2 directly, superantigens potently enhance the avidity between B7-2 and CD28, inducing thereby T-cell hyperactivation. Using the same 12-aa β-strand-hinge-α-helix domain, superantigens engage both B7-2 and CD28 at their homodimer interfaces, areas remote from where these coreceptors interact, implying that inflammatory signaling can be controlled through the receptor homodimer interfaces...
October 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Manojkumar Bupathi, Joud Hajjar, Stacie Bean, Siqing Fu, David Hong, Daniel Karp, Bettzy Stephen, Kenneth Hess, Funda Meric-Bernstam, Aung Naing
Infusion reactions (IRs) to anti-neoplastic agents require prompt recognition and immediate treatment to avert significant complications. We conducted a retrospective review of the medical records of consecutive patients who received anti-neoplastic therapy in the outpatient treatment center of the Department of Investigational Cancer Therapeutics from January 1, 2013 to November 30, 2013. Of the 597 patients who received treatment, 9 (1.5 %) had IRs (all ≤ grade 2). The most common IRs observed on first occurrence were chills (n = 5), itching, rash, and facial flushing (n = 3 each)...
September 29, 2016: Investigational New Drugs
Victoria Anne Saites, Rachel Hadler, Jacob Thomas Gutsche, Krzysztof Laudanski
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a rare hematological disease characterized by an excessive inflammatory response to various triggers, resulting in rapid multi-organ failure. Its incidence may be underestimated due to its rarity, its variable clinical presentation, and its high mortality rate prior to diagnosis. Oftentimes, HLH is mistaken for refractory sepsis and improperly treated as such. Left untreated, the disease is universally fatal. With treatment, case series of adults with HLH report a 30-day mortality of up to 44% and an overall mortality of up to 75%...
September 27, 2016: American Journal of Case Reports
Piero Ruscitti, Paola Cipriani, Francesco Ciccia, Francesco Masedu, Vasiliki Liakouli, Francesco Carubbi, Onorina Berardicurti, Giuliana Guggino, Paola Di Benedetto, Salvatore Di Bartolomeo, Marco Valenti, Giovanni Triolo, Roberto Giacomelli
Macrophage activation syndrome (MAS) is a rare, life-threatening disease in which early diagnosis and aggressive therapeutic strategy may improve the outcome. Due to its rarity, epidemiologic data are still lacking. Hyperferritinemia is frequently associated with MAS and might modulate the cytokine storm, which is involved in the development of multiple organ failure. In this paper, we investigated clinical data, treatments, and outcome of a homogeneous cohort of 41 adult MAS patients, complicating autoimmune rheumatic diseases...
September 21, 2016: Autoimmunity Reviews
Shelley Anne Adamo, Ilya Kovalko, Kurtis F Turnbull, Russell H Easy, Carol I Miles
Some parasites alter the behaviour of their hosts. The larvae of the parasitic wasp Cotesia congregata develop within the body of the caterpillar Manduca sexta During the initial phase of wasp development, the host's behaviour remains unchanged. However, once the wasps begin to scrape their way out of the caterpillar, the caterpillar host stops feeding and moving spontaneously. We found that the caterpillar also temporarily lost sensation around the exit hole created by each emerging wasp. However, the caterpillars regained responsiveness to nociception in those areas within 1 day...
September 15, 2016: Journal of Experimental Biology
Sheila M Keating, John W Heitman, Shiquan Wu, Xutao Deng, Andrea R Stacey, Roland C Zahn, Maurus de la Rosa, Samantha L Finstad, Jeffrey D Lifson, Michael Piatak, Marie-Claire Gauduin, Benedikt M Kessler, Nicola Ternette, Angela Carville, R Paul Johnson, Ronald C Desrosiers, Norman L Letvin, Persephone Borrow, Philip J Norris, Joern E Schmitz
: Acute HIV infection represents a period of intense immune perturbation and activation of the host immune system. Study of the eclipse and viral expansion phases of infection is difficult in humans, but studies in non-progressive and progressive nonhuman primate infection models can provide significant insight into critical events occurring during this time. Cytokines, chemokines and other soluble immune factors were measured in longitudinal samples from rhesus macaques infected with either SIVmac251 (progressive infection) or SIVmac239Δnef (attenuated/non-progressive infection), and from African green monkeys infected with SIVsab9315BR (non-pathogenic infection)...
September 14, 2016: Journal of Virology
Isaac Ginsburg, Erez Koren, James Varani, Ron Kohen
In 2009, Xu et al. and Chaput et al. in Nature Medicine had argued that the main cause of death in sepsis is the release from neutrophil nets of nuclear histone, highly toxic to endothelial cells and that these polycations are major and unique virulence factors. Since 2009, numerous researchers have also suggested the involvement of histones in the pathophysiology of many clinical disorders. If histones are indeed major unique virulence toxic agents, then heparin, activated protein C and antibodies to histone should prove excellent antisepsis agents...
October 2016: Inflammopharmacology
G Lachmann, P La Rosée, T Schenk, F M Brunkhorst, C Spies
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) has well been studied as a genetic disorder in children (primary HLH). Mutations in the regulatory complex of the cellular immune synapse lead to a loss of function of cytotoxic T‑cells and natural killer cells with excessive inflammation based on a cytokine storm. During the last decade, an increasing number of adult HLH patients without a family history of HLH (secondary or acquired HLH) have been reported. Various triggers - infections, malignancies or autoimmune diseases - result in an acquired loss of function of these cells and a sepsis-like disease...
October 2016: Der Anaesthesist
Dmitry Tyrsin, Sergey Chuvpilo, Alexey Matskevich, Daniil Nemenov, Paula S Römer, Paula Tabares, Thomas Hünig
CD28 superagonists (CD28SA) are CD28-specific monoclonal antibodies which are able to activate T-cells without overt TCR engagement. In rodents, CD28SA efficiently activate regulatory T-cells and are therapeutically effective in multiple models of autoimmunity, inflammation and transplantation. However, a phase I study of the human CD28SA TGN1412 in 2006 resulted in a life-threatening cytokine storm. This brief review summarises preclinical work before and since the failed phase I trial with an emphasis on understanding the reasons why there had been no warning of toxicity, and how a novel assay paved the way for a new phase I, phase Ib (both completed), and an ongoing phase II study...
July 2016: Clinical and Experimental Rheumatology
Ji Young Lee, Helena M Linge, Kanta Ochani, Ke Lin, Edmund J Miller
INTRODUCTION: Sepsis is characterized by dysregulated systemic inflammation and cytokine storm. Angiopoietin-2 (Ang-2) is known to closely correlate with severity of sepsis-related acute lung injury and mortality. The aim of this study was to clarify the mechanisms involved in Ang-2 secretion to better understand the pathophysiology of sepsis. MATERIALS AND METHODS: The concentration of Ang-2 was assessed in culture medium of pulmonary microvascular endothelial cells in the presence or absence of Gram-positive bacteria cell wall components [lipoteichoic acid (LTA) and peptidoglycan (PGN)] stimulation at different time points ranging from 15 minutes to 24 hours...
September 1, 2016: Experimental Lung Research
Maddison Jade Griffin, Hayley Louise Letson, Geoffrey Phillip Dobson
Innovative host-directed drug therapies are urgently required to treat sepsis. We tested the effect of small-volume 0.9% NaCl adenosine, lidocaine and Mg(2+) (ALM) bolus and 4 hour intravenous infusion on survivability in the rat model of polymicrobial sepsis over 6 days. ALM treatment led to a significant increase in survivability (88%) compared to controls (25%). Four controls died on Days 2-3 and two died on Day 5. Early death was associated with elevated plasma and lung inflammatory markers (IL-6, IL-1ß, C-reactive protein), reduced white blood cell count (WBC), hypoxemia, hypercapnia, acidosis, hyperkalemia and elevated lactate, whereas late death was associated with a massive cytokine storm, a neutrophil dominated WBC rebound/overshoot, increased lung oxidant injury, edema and persistent ischemia...
August 31, 2016: Clinical and Vaccine Immunology: CVI
Yury Oliveira Chaves, Allyson Guimarães da Costa, Marcelo Luís Monteiro Pereira, Marcus Vinícius Guimarães de Lacerda, Jordana Grazziela Coelho-Dos-Reis, Olindo Assis Martins-Filho, Andréa Teixeira-Carvalho, Adriana Malheiro, Wuelton Marcelo Monteiro, Patrícia Puccinelli Orlandi, Claudio Romero Farias Marinho, Paulo Afonso Nogueira
BACKGROUND: Plasmodium vivax is the causative agent of human malaria of large geographic distribution, with 35 million cases annually. In Brazil, it is the most prevalent species, being responsible by around 70 % of the malaria cases. METHODS: A cross-sectional study was performed in Manaus (Amazonas, Brazil), including 36 adult patients with primary malaria, 19 with recurrent malaria, and 20 endemic controls. The ex vivo phenotypic features of circulating leukocyte subsets (CD4(+) T-cells, CD8(+) T-cells, NK, NKT, B, B1 and Treg cells) as well as the plasmatic cytokine profile (IL-2, IL-4, IL-6, IL-10, TNF and IFN-γ) were assessed, aiming at establishing patterns of immune response characteristic of primary malaria vs recurrent malaria as compared to endemic controls...
2016: Malaria Journal
Hiroshi Kido, Irene L Indalao, Hyejin Kim, Takashi Kimoto, Satoko Sakai, Etsuhisa Takahashi
Severe influenza is characterized by cytokine storm and multiorgan failure. Influenza patients with underlying diseases show a rapid progression in disease severity. The major mechanism that underlies multiorgan failure during the progressive stage of infection, particularly in patients with underlying risk factors, is mitochondrial energy crisis. The relationship between the factors that determine infection severity, such as influenza virus, cytokines, cellular trypsin as a hemagglutinin processing protease for viral multiplication, accumulation of metabolic intermediates and ATP crisis in mitochondria, is termed the "influenza virus-cytokine-trypsin" cycle...
September 2016: Respiratory Investigation
Lianwen Zhang, Michael B Steele, Nathan Jenks, Jacquelyn Grell, Lukkana Suksanpaisan, Shruthi Naik, Mark J Federspiel, Martha Q Lacy, Stephen J Russell, Kah-Whye Peng
Oncolytic VSV-IFNβ-NIS is selectively destructive to tumors. Here, we present the IND enabling preclinical rodent studies in support of clinical testing of vesicular stomatitis virus (VSV) as a systemic therapy. Efficacy studies showed dose-dependent tumor regression in C57BL/KaLwRij mice bearing syngeneic 5TGM1 plasmacytomas after systemic VSV administration. In contrast, the virus was effective at all doses tested against human KAS6/1 xenografts in SCID mice. Intravenous administration of VSV-mIFNβ-NIS is well tolerated in C57BL/6 mice up to 5 × 10(10) TCID50 (50% tissue culture infective dose)/kg with no neurovirulence, no cytokine storm, and no abnormalities in tissues...
September 2016: Human Gene Therapy. Clinical Development
E Scott Halstead, Surender Rajasekaran, Julie C Fitzgerald, Scott L Weiss
We describe a case of an infant with HSV meningitis and septic shock who demonstrated a remarkably high serum ferritin level. Aggressive pediatric intensive care and the administration of high-dose glucocorticoids were not able to reverse the multiple organ dysfunctions. Subsequent autopsy identified the presence of hemophagocytosis, thus the patient fulfilled hemophagocytic lymphohistiocytosis (HLH) criteria post-mortem. This case highlights that serum ferritin may be an important early indicator of mortality in sepsis due to a cytokine storm similar to macrophage activation syndrome and HLH...
2016: Frontiers in Pediatrics
Yao Yao, Hai Deng, Pingfei Li, Jian Zhang, Junbo Zhang, Deping Wang, Songbo Li, Yixing Luo, Zhengping Wei, Guoyu Bi, Xiang-Ping Yang, Zhao-Hui Tang
Sepsis is the leading cause of death among critically ill patients and NKT cell activation is essential to induce inflammatory cytokines cascade in sepsis. However, little is known about what regulates the NKT cell function during sepsis. Herein, we showed Tim-3 expression in NKT cells is elevated in experimental mice during sepsis. Tim-3 expression was positively correlated with NKT cell activation and apoptosis. In sepsis, IL-12 secreted by DCs exposure to LPS increased the expression of Tim-3 in NKT cells...
August 8, 2016: Shock
David A Khan
OBJECTIVE: There has been a great expanse in the use of biological agents during the past decade. However, there are significant differences between biologics and typical pharmaceutical drugs. This review focuses on 3 separate types of adverse reactions to biologics, namely high cytokine reactions, hypersensitivity reactions, and secondary immunodeficiency. DATA SOURCES: A PubMed literature search restricted to the previous 10 years using combinations of search terms, including omalizumab, rituximab, TGN1412, biologic agent, anaphylaxis, hypogammaglobulinemia, desensitization, and cytokine storm, was performed...
August 2016: Annals of Allergy, Asthma & Immunology
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