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1.
Nat Rev Immunol ; 22(2): 85-96, 2022 02.
Article in English | MEDLINE | ID: covidwho-2133458

ABSTRACT

A paradigm shift has recently occurred in the field of cancer therapeutics. Traditional anticancer agents, such as chemotherapy, radiotherapy and small-molecule drugs targeting specific signalling pathways, have been joined by cellular immunotherapies based on T cell engineering. The rapid adoption of novel, patient-specific cellular therapies builds on scientific developments in tumour immunology, genetic engineering and cell manufacturing, best illustrated by the curative potential of chimeric antigen receptor (CAR) T cell therapy targeting CD19-expressing malignancies. However, the clinical benefit observed in many patients may come at a cost. In up to one-third of patients, significant toxicities occur that are directly associated with the induction of powerful immune effector responses. The most frequently observed immune-mediated toxicities are cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This Review discusses our current understanding of their pathophysiology and clinical features, as well as the development of novel therapeutics for their prevention and/or management.


Subject(s)
Neoplasms , Neurotoxicity Syndromes , Antigens, CD19 , Cytokine Release Syndrome/etiology , Humans , Immunotherapy/adverse effects , Immunotherapy, Adoptive/adverse effects , Neoplasms/drug therapy , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/etiology , Receptors, Antigen, T-Cell/genetics
2.
Infect Dis Clin North Am ; 36(4): 735-748, 2022 12.
Article in English | MEDLINE | ID: covidwho-2095433

ABSTRACT

Both cytokine release syndrome (CRS) and sepsis are clinical syndromes rather than distinct diseases and share considerable overlap. It can often be challenging to distinguish between the two, but it is important given the availability of targeted treatment options. In addition, several other clinical syndromes overlap with CRS and sepsis, further making it difficult to differentiate them. This has particularly been highlighted in the recent coronavirus disease-2019 pandemic. As we start to understand the differences in the inflammatory markers and presentations in these syndromes, hopefully we will be able to enhance treatment and improve outcomes.


Subject(s)
COVID-19 , Sepsis , Humans , Cytokine Release Syndrome/etiology , Antibodies, Monoclonal, Humanized/therapeutic use , Interleukin-6 , Sepsis/drug therapy
3.
Rev Esp Quimioter ; 35 Suppl 3: 6-9, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2091721

ABSTRACT

In response to SARS-CoV-2 infection, the immune system physiologically upregulates to try to clear the virus from the body; failure to compensate for this inflammatory response with an anti-inflammatory response leads to dysregulation of the immune system that ultimately leads to a situation of uncontrolled hyperinflammation called cytokine storm. This cytokine storm can cause ARDS or multi-organ failure leading to patient death. This review exposes the different mechanisms of the inflammatory response in COVID-19 infection and the therapeutic options to treat this process.


Subject(s)
COVID-19 , Humans , COVID-19/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , SARS-CoV-2 , Cytokines , Anti-Inflammatory Agents/therapeutic use
4.
Transfus Apher Sci ; 61(4): 103433, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-2016139

ABSTRACT

The risk of mortality in patients with coronavirus disease 2019 (COVID-19) is largely related to an excessive immune response, resulting in a hyperinflammatory and hypercoagulable condition collectively referred to as cytokine storm syndrome (CSS). Management of critically ill patients with COVID-19 has included attempts to abate this process, prevent disease progression, and reduce mortality. In this context, therapeutic plasma exchange (TPE) offers an approach to eliminate inflammatory factors and cytokines, offset the pathologic coagulopathy, and reduce the CSS effects. The aim of this review is to analyze available data on the use of TPE for the treatment of CSS in patients with COVID-19. Systematic searches of PubMed, Scopus and COVID-19 Research were conducted to identify articles published between March 1, 2020 and May 26, 2021 reporting the use of TPE for the treatment of COVID-19-induced CSS. A total of 34 peer-reviewed articles (1 randomized controlled trial, 4 matched case-control series, 15 single-group case series, and 14 case reports), including 267 patients, were selected. Despite the low evidence level of the available data, TPE appeared to be a safe intervention for critically ill patients with COVID-19-induced CSS. Although inconsistencies exist between studies, they showed a general trend for decreased interleukin-6, C-reactive protein, ferritin, D-dimer, and fibrinogen levels and increased lymphocyte counts following TPE, supporting the immunomodulatory effect of this treatment. Moreover, TPE was associated with improvements in clinical outcomes in critically ill patients with COVID-19. While TPE may offer a valuable option to treat patients with COVID-19-induced CSS, high-quality randomized controlled clinical trials are needed to confirm its potential clinical benefits, feasibility, and safety. Moreover, clear criteria should be established to identify patients with CSS who might benefit from TPE.


Subject(s)
COVID-19 , COVID-19/complications , COVID-19/therapy , Critical Illness/therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/therapy , Humans , Plasma Exchange , Randomized Controlled Trials as Topic , SARS-CoV-2
5.
BMC Infect Dis ; 22(1): 537, 2022 Jun 13.
Article in English | MEDLINE | ID: covidwho-1986768

ABSTRACT

BACKGROUND: Passive immunization against SARS-CoV-2 limits viral burden and death from COVID-19; however, it poses a theoretical risk of disease exacerbation through antibody-dependent enhancement (ADE). ADE after anti-SARS-CoV2 antibody treatment has not been reported, and therefore the potential risk and promoting factors remain unknown. CASE PRESENTATION: A 75-year-old female was admitted to the emergency room with recurrent, unexplained bruises and leukocytopenia, anemia, and thrombocytopenia. Evaluation of a bone marrow biopsy established the diagnosis of an acute promyelocytic leukemia (APL). SARS-CoV-2 RT-PCR testing of nasal and throat swabs on admission was negative. During the routine SARS-CoV-2 testing of inpatients, our patient tested positive for SARS-CoV-2 on day 14 after admission without typical COVID-19 symptoms. Due to disease- and therapy-related immunosuppression and advanced age conferring a high risk of progressing to severe COVID-19, casirivimab and imdevimab were administered as a preemptive approach. The patient developed immune activation and cytokine release syndrome (CRS) occurring within four hours of preemptive anti-SARS-CoV2 antibody (casirivimab/imdevimab) infusion. Immune activation and CRS were evidenced by a rapid increase in serum cytokines (IL-6, TNFα, IL-8, IL-10), acute respiratory insufficiency, and progressive acute respiratory distress syndrome. DISCUSSION AND CONCLUSION: The temporal relationship between therapeutic antibody administration and the rapid laboratory, radiological, and clinical deterioration suggests that CRS was an antibody-related adverse event, potentially exacerbated by APL treatment-mediated differentiation of leukemic blasts and promyelocytes. This case highlights the need for careful assessment of life-threatening adverse events after passive SARS-CoV-2 immunization, especially in the clinical context of patients with complex immune and hematological landscapes.


Subject(s)
COVID-19 , Leukemia, Promyelocytic, Acute , Respiratory Distress Syndrome , Aged , Antibodies, Monoclonal, Humanized , COVID-19/complications , COVID-19/diagnosis , COVID-19 Testing , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Female , Humans , Leukemia, Promyelocytic, Acute/complications , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , SARS-CoV-2
6.
Ann Afr Med ; 21(2): 168-172, 2022.
Article in English | MEDLINE | ID: covidwho-1954255

ABSTRACT

COVID-19 is a viral disease that commonly presents with mild symptoms with predominant respiratory system involvement. However, it can cause serious complications such as acute respiratory disease, multi-organ dysfunction, especially in patients with comorbidities. As it is a new disease, the full picture of the disease and its complications are not yet fully understood. Moreover, the patients at risk of complications are not well identified, and the data about the biphasic pattern of cytokine storm syndrome are limited. Here, we report the case of a 64-year-old male having diabetes mellitus, hypertension, ischemic heart disease with triple-vessel coronary artery disease tested positive for severe acute respiratory syndrome coronavirus 2, then complicated with acute respiratory distress syndrome and two waves of cytokine storm in 28 days.


Résumé La COVID-19 est une maladie virale qui se présente généralement avec des symptômes bénins avec une atteinte prédominante du système respiratoire. Cependant, il peut entraîner des complications graves telles qu'une maladie respiratoire aiguë, un dysfonctionnement multiviscéral, en particulier chez les patients présentant des comorbidités. Comme il s'agit d'une nouvelle maladie, l'image complète de la maladie et de ses complications n'est pas encore entièrement comprise. De plus, les patients à risque de complications ne sont pas bien identifiés et les données sur le schéma biphasique du syndrome de tempête de cytokines sont limitées. Nous rapportons ici le cas d'un homme de 64 ans ayant un diabète sucré, une hypertension, une cardiopathie ischémique avec coronaropathie tri-vasculaire testé positif au syndrome respiratoire aigu sévère coronavirus 2, puis compliqué d'un syndrome de détresse respiratoire aiguë et deux vagues de tempête de cytokines en 28 jours. Mots-clés: Syndrome de détresse respiratoire aiguë, pneumonie COVID-19, tempête de cytokines, hyperinflammation.


Subject(s)
COVID-19 , Cytokine Release Syndrome , COVID-19/complications , Cytokine Release Syndrome/etiology , Humans , Male , Middle Aged , SARS-CoV-2
7.
Int J Mol Sci ; 23(12)2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1884212

ABSTRACT

Coronavirus 2019 disease (COVID-19) is caused by different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in December of 2019. COVID-19 pathogenesis is complex and involves a dysregulated renin angiotensin system. Severe courses of the disease are associated with a dysregulated immunological response known as cytokine storm. Many scientists have demonstrated that SARS-CoV-2 impacts oxidative homeostasis and stimulates the production of reactive oxygen species (ROS). In addition, the virus inhibits glutathione (GSH) and nuclear factor erythroid 2-related factor 2 (NRF2)-a major antioxidant which induces expression of protective proteins and prevents ROS damage. Furthermore, the virus stimulates NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes which play a significant role in inducing a cytokine storm. A variety of agents with antioxidant properties have shown beneficial effects in experimental and clinical studies of COVID-19. This review aims to present mechanisms of oxidative stress induced by SARS-CoV-2 and to discuss whether antioxidative drugs can counteract detrimental outcomes of a cytokine storm.


Subject(s)
COVID-19 , Antioxidants/metabolism , Antioxidants/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Humans , Oxidative Stress , Reactive Oxygen Species , SARS-CoV-2
9.
Curr Drug Targets ; 23(12): 1136-1154, 2022.
Article in English | MEDLINE | ID: covidwho-1793194

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is currently rampant worldwide, resulting in unpredictable harm to humans. High blood levels of cytokines and chemokines have been marked in patients with COVID-19 infection, leading to cytokine storm syndrome. Cytokine storms are violent inflammatory immune responses that reveal the devastating effect of immune dysregulation and the critical role of an effective host immune response. METHODS: Scientometric analysis summarizes the literature on cytokine storms in recent decades and provides a valuable and timely approach to tracking the development of new trends. This review summarizes the pathogenesis and treatment of diseases associated with cytokine storms comprehensively based on scientometric analysis. RESULTS: Field distribution, knowledge structure, and research topic evolution correlated with cytokine storms are revealed, and the occurrence, development, and treatment of disease relevant to cytokine storms are illustrated. CONCLUSION: Cytokine storms can be induced by pathogens and iatrogenic causes and can also occur in the context of autoimmune diseases and monogenic diseases as well. These reveal the multidisciplinary nature of cytokine storms and remind the complexity of the pathophysiological features, clinical presentation, and management. Overall, this scientometric study provides a macroscopic presentation and further direction for researchers who focus on cytokine storms.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Cytokine Release Syndrome/etiology , Cytokines , Humans , SARS-CoV-2
10.
Cancer Metastasis Rev ; 41(1): 1-15, 2022 03.
Article in English | MEDLINE | ID: covidwho-1708847

ABSTRACT

Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an ongoing pandemic causing significant morbidity and mortality worldwide. The "cytokine storm" is a critical driving force in severe COVID-19 cases, leading to hyperinflammation, multi-system organ failure, and death. A paradigm shift is emerging in our understanding of the resolution of inflammation from a passive course to an active biochemical process driven by endogenous specialized pro-resolving mediators (SPMs), such as resolvins, protectins, lipoxins, and maresins. SPMs stimulate macrophage-mediated debris clearance and counter pro-inflammatory cytokine production, a process collectively termed as the "resolution of inflammation." Hyperinflammation is not unique to COVID-19 and also occurs in neoplastic conditions, putting individuals with underlying health conditions such as cancer at elevated risk of severe SARS-CoV-2 infection. Despite approaches to block systemic inflammation, there are no current therapies designed to stimulate the resolution of inflammation in patients with COVID-19 or cancer. A non-immunosuppressive therapeutic approach that reduces the cytokine storm in patients with COVID-19 and cancer is urgently needed. SPMs are potent immunoresolvent and organ-protective lipid autacoids that stimulate the resolution of inflammation, facilitate clearance of infections, reduce thrombus burden, and promote a return to tissue homeostasis. Targeting endogenous lipid mediators, such as SPMs, offers an entirely novel approach to control SARS-CoV-2 infection and cancer by increasing the body's natural reserve of pro-resolving mediators without overt toxicity or immunosuppression.


Subject(s)
COVID-19 , Neoplasms , Cytokine Release Syndrome/etiology , Humans , Inflammation , Pandemics , SARS-CoV-2
11.
Purinergic Signal ; 18(1): 13-59, 2022 03.
Article in English | MEDLINE | ID: covidwho-1694363

ABSTRACT

Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.


Subject(s)
Adenosine Triphosphate/metabolism , COVID-19/immunology , Cytokine Release Syndrome/etiology , Inflammation/etiology , Lidocaine/therapeutic use , Purinergic P2X Receptor Antagonists/therapeutic use , Receptors, Purinergic/physiology , Anti-Inflammatory Agents/therapeutic use , Critical Care , Cytokine Release Syndrome/drug therapy , Humans , Inflammation/drug therapy , Infusions, Subcutaneous , Lidocaine/administration & dosage , Lidocaine/pharmacology , Lymph Nodes/immunology , Lymphatic System/immunology , Male , Maximum Tolerated Dose , Middle Aged , Models, Immunological , Purinergic P2X Receptor Antagonists/administration & dosage , Purinergic P2X Receptor Antagonists/pharmacology , Receptors, Purinergic/drug effects , Receptors, Purinergic P1/drug effects , Receptors, Purinergic P1/physiology , Receptors, Purinergic P2X7/physiology , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Signal Transduction , T-Lymphocytes, Regulatory/immunology
12.
Clin Exp Pharmacol Physiol ; 49(4): 483-491, 2022 04.
Article in English | MEDLINE | ID: covidwho-1691664

ABSTRACT

Progress in the study of Covid-19 disease in rodents has been hampered by the lack of angiotensin-converting enzyme 2 (ACE2; virus entry route to the target cell) affinities for the virus spike proteins across species. Therefore, we sought to determine whether a modified protocol of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome in rats can mimic both cell signalling pathways as well as severe disease phenotypes of Covid-19 disease. Rats were injected via intratracheal (IT) instillation with either 15 mg/kg of LPS (model group) or saline (control group) before being killed after 3 days. A severe acute respiratory syndrome (SARS)-like effect was observed in the model group as demonstrated by the development of a "cytokine storm" (>2.7 fold increase in blood levels of IL-6, IL-17A, GM-CSF, and TNF-α), high blood ferritin, demonstrable coagulopathy, including elevated D-dimer (approximately 10-fold increase), PAI-1, PT, and APTT (p < 0.0001). In addition, LPS increased the expression of lung angiotensin II type I receptor (AT1R)-JAK-STAT axis (>4 fold increase). Chest imaging revealed bilateral small patchy opacities of the lungs. Severe lung injury was noted by the presence of both, alveolar collapse and haemorrhage, desquamation of epithelial cells in the airway lumen, infiltration of inflammatory cells (CD45+ leukocytes), widespread thickening of the interalveolar septa, and ultrastructural alterations similar to Covid-19. Thus, these findings demonstrate that IT injection of 15 mg/kg LPS into rats, induced an AT1R/JAK/STAT-mediated cytokine storm with resultant pneumonia and coagulopathy that was commensurate with moderate and severe Covid-19 disease noted in humans.


Subject(s)
Acute Lung Injury/etiology , Blood Coagulation Disorders/etiology , COVID-19/pathology , Cytokine Release Syndrome/etiology , Hemorrhage/etiology , Lipopolysaccharides/adverse effects , Lung Diseases/etiology , Receptor, Angiotensin, Type 1/metabolism , STAT Transcription Factors/metabolism , Signal Transduction , Acute Lung Injury/pathology , Animals , Blood Coagulation Disorders/pathology , COVID-19/etiology , Cytokine Release Syndrome/pathology , Disease Models, Animal , Hemorrhage/pathology , Janus Kinases , Lung Diseases/pathology , Male , Rats , Rats, Wistar
13.
Rev Med Virol ; 32(6): e2334, 2022 11.
Article in English | MEDLINE | ID: covidwho-1669638

ABSTRACT

With the progression of investigations on the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), neurological complications have emerged as a critical aspect of the ongoing coronavirus disease 2019 (Covid-19) pandemic. Besides the well-known respiratory symptoms, many neurological manifestations such as anosmia/ageusia, headaches, dizziness, seizures, and strokes have been documented in hospitalised patients. The neurotropism background of coronaviruses has led to speculation that the neurological complications are caused by the direct invasion of SARS-CoV-2 into the nervous system. This invasion is proposed to occur through the infection of peripheral nerves or via systemic blood circulation, termed neuronal and haematogenous routes of invasion, respectively. On the other hand, aberrant immune responses and respiratory insufficiency associated with Covid-19 are suggested to affect the nervous system indirectly. Deleterious roles of cytokine storm and hypoxic conditions in blood-brain barrier disruption, coagulation abnormalities, and autoimmune neuropathies are well investigated in coronavirus infections, as well as Covid-19. Here, we review the latest discoveries focussing on possible molecular mechanisms of direct and indirect impacts of SARS-CoV-2 on the nervous system and try to elucidate the link between some potential therapeutic strategies and the molecular pathways.


Subject(s)
COVID-19 , Nervous System Diseases , Humans , COVID-19/complications , SARS-CoV-2 , Pandemics , Nervous System Diseases/etiology , Nervous System Diseases/epidemiology , Cytokine Release Syndrome/etiology
14.
Int J Biol Sci ; 18(2): 459-472, 2022.
Article in English | MEDLINE | ID: covidwho-1667649

ABSTRACT

The COVID-19 outbreak is emerging as a significant public health challenge. Excessive production of proinflammatory cytokines, also known as cytokine storm, is a severe clinical syndrome known to develop as a complication of infectious or inflammatory diseases. Clinical evidence suggests that the occurrence of cytokine storm in severe acute respiratory syndrome secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely associated with the rapid deterioration and high mortality of severe cases. In this review, we aim to summarize the mechanism of SARS-CoV-2 infection and the subsequent immunological events related to excessive cytokine production and inflammatory responses associated with ACE2-AngII signaling. An overview of the diagnosis and an update on current therapeutic regimens and vaccinations is also provided.


Subject(s)
COVID-19/complications , COVID-19/pathology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/pathology , SARS-CoV-2 , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation/immunology , Humans
15.
Sci Rep ; 12(1): 1626, 2022 01 31.
Article in English | MEDLINE | ID: covidwho-1661980

ABSTRACT

The ongoing COVID-19 pandemic is one of the biggest health challenges of recent decades. Among the causes of mortality triggered by SARS-CoV-2 infection, the development of an inflammatory "cytokine storm" (CS) plays a determinant role. Here, we used transcriptomic data from the bronchoalveolar lavage fluid (BALF) of COVID-19 patients undergoing a CS to obtain gene-signatures associated to this pathology. Using these signatures, we interrogated the Connectivity Map (CMap) dataset that contains the effects of over 5000 small molecules on the transcriptome of human cell lines, and looked for molecules which effects on transcription mimic or oppose those of the CS. As expected, molecules that potentiate immune responses such as PKC activators are predicted to worsen the CS. In addition, we identified the negative regulation of female hormones among pathways potentially aggravating the CS, which helps to understand the gender-related differences in COVID-19 mortality. Regarding drugs potentially counteracting the CS, we identified glucocorticoids as a top hit, which validates our approach as this is the primary treatment for this pathology. Interestingly, our analysis also reveals a potential effect of MEK inhibitors in reverting the COVID-19 CS, which is supported by in vitro data that confirms the anti-inflammatory properties of these compounds.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Computer Simulation , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Glucocorticoids/therapeutic use , Pandemics , Protein Kinase Inhibitors/therapeutic use , SARS-CoV-2 , Anti-Inflammatory Agents/pharmacology , Bronchoalveolar Lavage Fluid/virology , COVID-19/blood , COVID-19/epidemiology , Cytokine Release Syndrome/mortality , Cytokines/blood , Female , Gene Expression Profiling/methods , Glucocorticoids/pharmacology , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , MAP Kinase Signaling System/drug effects , Male , Protein Kinase Inhibitors/pharmacology , Sex Factors , Transcriptome/genetics
16.
Clin Immunol ; 236: 108936, 2022 03.
Article in English | MEDLINE | ID: covidwho-1650423

ABSTRACT

A 52-year-old male patient who was diagnosed with chronic lymphocytic leukemia two years ago; admitted to our hospital with complaints of fever (>38C), shortness of breath, and fatigue. He was receiving fludarabine, cyclophosphamide, and rituximab (FCR) regimen for one year after two courses of cyclophosphamide, vincristine, and prednisolone (CVP) regimen. The patient was diagnosed with COVID-19 associated cytokine storm and tocilizumab 800 mg was administered in addition to corticosteroids. Significant improvement was observed in both clinical and laboratory parameters and his hypoxemia resolved. The patient whose complaints recurred on the 13 th day of discharge was admitted to the hospital again with severe hypoxemia (oxygen saturation < 90) and fever (>38C). Pulse steroid (250 mg methylprednisolone for three days, followed by 40 mg/day) and anakinra 400 mg/day intravenously were started. Despite the treatment, the patient progressed to respiratory failure and died on the sixth day of second hospitalization.


Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Antineoplastic Combined Chemotherapy Protocols , COVID-19/complications , COVID-19/drug therapy , Cyclophosphamide/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Methylprednisolone/therapeutic use , Middle Aged , Rituximab/therapeutic use , Treatment Outcome
17.
Exp Biol Med (Maywood) ; 247(4): 330-337, 2022 02.
Article in English | MEDLINE | ID: covidwho-1649719

ABSTRACT

Cytokine storm is an umbrella term that describes an inflammatory syndrome characterized by elevated levels of circulating cytokines and hyperactivation of innate and/or adaptive immune cells. One type of cytokine storm is hemophagocytic lymphohistiocytosis (HLH), which can be either primary or secondary. Severe COVID-19-associated pneumonia and acute respiratory distress syndrome (ARDS) can also lead to cytokine storm/cytokine release syndrome (CS/CRS) and, more rarely, meet criteria for the diagnosis of secondary HLH. Here, we review the immunobiology of primary and secondary HLH and examine whether COVID-19-associated CS/CRS can be discriminated from non-COVID-19 secondary HLH. Finally, we review differences in immunobiology between these different entities, which may inform both clinical diagnosis and treatment of patients.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/therapy , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Cytokine Release Syndrome/virology , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/therapy
18.
Mol Biol Rep ; 49(3): 2303-2309, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1648443

ABSTRACT

Global vaccination effort and better understanding of treatment strategies provided a ray of hope for improvement in COVID-19 pandemic, however, in many countries, the disease continues to collect its death toll. The major pathogenic mechanism behind severe cases associated with high mortality is the burst of pro-inflammatory cytokines TNF, IL-6, IFNγ and others, resulting in multiple organ failure. Although the exact contribution of each cytokine is not clear, we provide an evidence that the central mediator of cytokine storm and its devastating consequences may be TNF. This cytokine is known to be involved in activated blood clotting, lung damage, insulin resistance, heart failure, and other conditions. A number of currently available pharmaceutical agents such as monoclonal antibodies and soluble TNF receptors can effectively prevent TNF from binding to its receptor(s). Other drugs are known to block NFkB, the major signal transducer molecule used in TNF signaling, or to block kinases involved in downstream activation cascades. Some of these medicines have already been selected for clinical trials, but more work is needed. A simple, rapid, and inexpensive method of directly monitoring TNF levels may be a valuable tool for a timely selection of COVID-19 patients for anti-TNF therapy.


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Pandemics , SARS-CoV-2 , Tumor Necrosis Factor Inhibitors/therapeutic use , Biomarkers , COVID-19/complications , COVID-19/metabolism , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Drug Repositioning , Humans , Interleukin-6/metabolism , Multiple Organ Failure/etiology , Multiple Organ Failure/prevention & control , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Patient Selection , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effects , Tumor Necrosis Factor Inhibitors/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/physiology
19.
J Infect Dev Ctries ; 15(12): 1825-1832, 2021 12 31.
Article in English | MEDLINE | ID: covidwho-1630926

ABSTRACT

INTRODUCTION: Tocilizumab, can be used in the treatment of COVID-19 in patients developing cytokine storms. This study retrospectively evaluated patients treated with Tocilizumab. METHODOLOGY: This study included 23 patients (17 men) admitted to the hospital and received Tocilizumab due to cytokine storms. The patients were categorized into three groups: "moderate, severe, and critical". Clinical outcomes after 7 days of hospitalization were classified as "death, disease aggravation, clinical stabilization, and clinical improvement". RESULTS: The mean age of the patients was 58±10.1 years. 52.2% of the patients were severely ill, and 47.8% were critically ill. After tocilizumab treatment, the mean lymphocyte count increased in all patients; the C-reactive protein levels dropped rapidly, except for one patient. After the first dose, the patients' fever dropped dramatically, and their oxygen support needs decreased. During the treatment, 82.6% of the patients were in the intensive care unit. At the end of the treatment, 56.5% had clinical improvement, 13% had clinical stabilization, and 4.3% had aggravation. Mortality occurred in 26.1%; 60.9% were discharged within a mean time of 19.14 ± 13.57 days after their treatment, and 18.2% of the critically ill and 91.7% of the severely ill patients recovered. CONCLUSIONS: Despite high rates of recovery and discharge after the tocilizumab treatment in the severely ill patients, more than half of the critically ill patients died. Early tocilizumab treatment resulted in a high survival rate and reduced the rates of progression to more critical states and mortality. Tocilizumab treatment should be given early in patients developing cytokine storms.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Aged , COVID-19/complications , COVID-19/mortality , Critical Illness , Cytokine Release Syndrome/etiology , Disease Progression , Female , Humans , Male , Middle Aged , Pandemics , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
20.
Front Immunol ; 12: 749291, 2021.
Article in English | MEDLINE | ID: covidwho-1566649

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. ß2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. ß-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, ß-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of ß-blockers in the management of Covid-19.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Sympathetic Nervous System/drug effects , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/metabolism , COVID-19/physiopathology , Catecholamines/metabolism , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/physiopathology , Cytokines/metabolism , Humans , /etiology , /physiopathology , SARS-CoV-2/pathogenicity , Sympathetic Nervous System/metabolism , Sympathetic Nervous System/physiopathology
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