Cytokine release syndrome. Reviewing a new entity in the intensive care unit

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DTC: doppler transcraneal; EEG: electroencefalograma; GCS: Glasgow Coma Score; HIC: hipertensión intracraneal; LP: lactato-piruvato; MD: microdiálisis; PIC: presión intracraneal; PPC: presión de perfusión cerebral; PtiO2: presión tisular de oxígeno; SjO2: saturación yugular de oxígeno; VM: ventilación mecánica. * Véase <a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a>." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Santafé Colomina, F. Arikan Abelló, A. Sánchez Corral, R. Ferrer Roca" "autores" => array:4 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Santafé Colomina" ] 1 => array:2 [ "nombre" => "F." "apellidos" => "Arikan Abelló" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Sánchez Corral" ] 3 => array:2 [ "nombre" => "R." 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Rodriguez Garcia, A. Medina, V. Modesto i Alapont, M.L. Palacios Loro, J. Mayordomo-Colunga, A. Vivanco-Allende, C. Rey" "autores" => array:7 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Rodriguez Garcia" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Medina" ] 2 => array:2 [ "nombre" => "V." "apellidos" => "Modesto i Alapont" ] 3 => array:2 [ "nombre" => "M.L." "apellidos" => "Palacios Loro" ] 4 => array:2 [ "nombre" => "J." "apellidos" => "Mayordomo-Colunga" ] 5 => array:2 [ "nombre" => "A." "apellidos" => "Vivanco-Allende" ] 6 => array:2 [ "nombre" => "C." "apellidos" => "Rey" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210569118301840?idApp=WMIE" "url" => "/02105691/0000004300000008/v1_201910220814/S0210569118301840/v1_201910220814/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Cytokine release syndrome. Reviewing a new entity in the intensive care unit" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "480" "paginaFinal" => "488" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Alejandra García Roche, Cándido Díaz Lagares, Elena Élez, Ricard Ferrer Roca" "autores" => array:4 [ 0 => array:3 [ "nombre" => "Alejandra" "apellidos" => "García Roche" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "Cándido" "apellidos" => "Díaz Lagares" "email" => array:1 [ 0 => "c.diaz@vhebron.net" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "Elena" "apellidos" => "Élez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Ricard" "apellidos" => "Ferrer Roca" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Intensive Care Department. SODIR Research Group. Vall d́Hebron University Hospital, Barcelona, España" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Intensive Care Department. SODIR Research Group. Vall d́Hebron University Hospital, Barcelona, España" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Medical Oncology Department. VHIO. Vall d́Hebron University Hospital, Barcelona, España" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Intensive Care Department. SODIR Research Group. Vall d́Hebron University Hospital, Barcelona, España" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author. Passeig de la Vall d́Hebron 119-129. Hospital Universitario Vall d́Hebron. 3ª planta. Servicio de Medicina Intensiva. CP 08035" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome de liberación de citocinas. Revisando una nueva enfermedad en la unidad de cuidados intensivos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1670 "Ancho" => 2168 "Tamanyo" => 232859 ] ] "descripcion" => array:1 [ "en" => "Clinical manifestations of cytokine release syndrome." ] ] ] "textoCompleto" => "BackgroundCancer is a mayor public health problem worldwide, expected to become the leading cause of death in many developed countries.<a class="elsevierStyleCrossRef" href="#bib0275">1</a> In Spain, it is the first cause of death in men and women over forty years, being responsible of 25% of global mortality.<a class="elsevierStyleCrossRef" href="#bib0280">2</a> During the last two decades, mortality has significantly dropped by means of more effective therapies, including immunotherapy, and improvement in supportive therapy,<a class="elsevierStyleCrossRef" href="#bib0285">3</a> reaching a 5 year survival around 50%.<a class="elsevierStyleCrossRef" href="#bib0280">2</a>Immunotherapy is a type of biological therapy <a class="elsevierStyleCrossRef" href="#bib0290">4</a> that seeks to harness the power of the immune system to eradicate malignant tissues,<a class="elsevierStyleCrossRef" href="#bib0295">5</a> while classic chemotherapy work by stopping or slowing the growth of cancer cells,<a class="elsevierStyleCrossRef" href="#bib0300">6</a> which is associated with immunosuppression and infection.<a class="elsevierStyleCrossRef" href="#bib0305">7</a> These new therapies include monoclonal antibodies (MAb), bispecific T-cell engaging (BiTe) therapy,<a class="elsevierStyleCrossRef" href="#bib0310">8</a> checkpoint inhibitors <a class="elsevierStyleCrossRef" href="#bib0305">7</a> and cellular therapies, as chimeric antigen receptor (CAR) T-cells 9 and T-infiltrating lymphocytes (TIL) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Despite showing impressive therapeutic success,<a class="elsevierStyleCrossRef" href="#bib0320">10</a> these therapies are also accompanied by severe and life-threatening adverse effects, as severe cytokine release syndrome (CRS) and autoimmunity.<a class="elsevierStyleCrossRef" href="#bib0325">11</a> CRS occurs as a result of massive release of cytokines after immunotherapy, while autoimmune occurs when the targeted tumor associated antigen is expressed on non malignant tissue, so-called “on target, off-tumor toxicity”.<a class="elsevierStyleCrossRef" href="#bib0295">5</a> CRS occurs mainly after BiTe and CAR T-cell therapy, with a quite variable incidence, ranging from 2% to 94%, reflecting different prophylactic approaches, variable doses, underreporting and variable CRS definitions.<a class="elsevierStyleCrossRefs" href="#bib0320">10,12,13</a> Checkpoint inhibitors despite occasionally related to CRS<a class="elsevierStyleCrossRef" href="#bib0340">14</a> are mainly associated with autoimmune events.<a class="elsevierStyleCrossRef" href="#bib0305">7</a> Isolated cases of CRS have been related to hematopoietic stem cell transplantation (HSCT),<a class="elsevierStyleCrossRef" href="#bib0345">15</a> and even conventional chemotherapy <a class="elsevierStyleCrossRef" href="#bib0325">11</a> and radiotherapy.<a class="elsevierStyleCrossRef" href="#bib0350">16</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>CRS was first described in 1989, in kidney transplant recipients treated with the anti-CD3 monoclonal antibody OKT3, which typically developed a flu-like syndrome one hour after the first infusion.<a class="elsevierStyleCrossRef" href="#bib0355">17</a> The syndrome became more relevant after 1997, with the approval of rituximab and a myriad of MAb for the treatment of different cancers, many of them also related to the presence of CRS.<a class="elsevierStyleCrossRefs" href="#bib0360">18,19</a> Later on, in 2006, a severe CRS (sCRS) was induced in 6 healthy volunteers who received an anti CD28 monoclonal antibody (TGN1412), requiring ICU admission for respiratory distress and renal failure.<a class="elsevierStyleCrossRef" href="#bib0370">20</a> In recent years, with the appearance of BiTe and cellular therapies, CRS has been increasingly reported.<a class="elsevierStyleCrossRef" href="#bib0325">11</a>Over the last two decades, the number of cancer patients requiring ICU care has dramatically increased, with 15% of ICU beds occupied by cancer patients.<a class="elsevierStyleCrossRef" href="#bib0285">3</a> With the extensive use of immunotherapy in cancer, CRS is being increasingly reported.<a class="elsevierStyleCrossRef" href="#bib0305">7</a>Thus, intensive care medicine will become a key component in the management of the complications of modern cancer therapies.<a class="elsevierStyleCrossRef" href="#bib0325">11</a> We will need to face patients with an over-active immune system, inducing severe organ dysfunction, while we try to keep the efficacy of the treatment. That is the new paradigm.MethodsWe performed a review searching In Medline (Pubmed) database using the term “cytokine release syndrome” restricted to articles with the selected term present in title or abstract [TiAb]. All articles identified by the search were initially screened for eligibility on title and abstract independently by two reviewers. The references of the selected articles were in turn used to identify additional studies. Any differences were resolved by consensus.PathophysiologyThe rising stars in cancer treatment (MAb, BiTe, CAR T-cell) are approaches by which the patient́s immunological self-defense is strengthened in a feasible and effective manner,<a class="elsevierStyleCrossRef" href="#bib0305">7</a> enhancing the power of the immune system to destroy cancer cells,<a class="elsevierStyleCrossRef" href="#bib0295">5</a> which can cause an excessive release of inflammatory cytokines,<a class="elsevierStyleCrossRef" href="#bib0375">21</a> leading to a severe systemic inflammatory response and multiple organ dysfunction.<a class="elsevierStyleCrossRef" href="#bib0380">22</a> The source of cytokines can be either target cells themselves or immune cells that have been recruited to the tumor site.<a class="elsevierStyleCrossRef" href="#bib0325">11</a>All these therapies, in different ways, cause a significant activation of the immune system,<a class="elsevierStyleCrossRef" href="#bib0320">10</a> including lymphocytes (B cells, T cells and/or natural killer cells) and/or myeloid cells (macrophages, dendritic cells, and monocytes) which lead to release of lymphocyte derived (IFN gamma, IL-6, sIL-2R alpha, sIL-6R, and GM-CSF) and monocyte/macrophage (IL1-receptor antagonist, IL-10, IL-6, IP-10, monokine, IFN alpha, MIP-1 alpha, MIP-1 beta, and sIL6R) cytokines.<a class="elsevierStyleCrossRef" href="#bib0375">21</a> IL-6 plays a central role in CRS.<a class="elsevierStyleCrossRef" href="#bib0295">5</a> There is also evidence of vascular endothelial activation and dysfunction that is triggered by IFN-gamma, IL-6 and TNF-alpha. Activated endothelial cells, in turn, produce more IL-6.<a class="elsevierStyleCrossRef" href="#bib0345">15</a> This excessive IL-6 activation leads to vascular leakage as well as activation of the complement and the coagulation cascade, leading to multiple organ dysfunction and disseminated intravascular coagulation.<a class="elsevierStyleCrossRefs" href="#bib0325">11,22</a> IL-6 increases the production of vascular endothelial grown factor, which internalizes vascular endothelial cadherin, a mayor structural protein that mediates adhesion of adjacent cells, leading to vascular leakage. The complement is also involved in increasing the permeability on endothelial cells, as IL-6 upregulates C5a receptors on endothelial cells and increases their responsiveness to C5a. IL-6 also induces tissue factor expression on the cell surface of monocytes, triggering coagulation cascade <a class="elsevierStyleCrossRef" href="#bib0380">22</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>). The pathophysiology of left ventricular (LV) dysfunction may be similar to that observed with sepsis induced and stress (Tako-Tsubo) cardiomyopathy.<a class="elsevierStyleCrossRef" href="#bib0385">23</a> IL-6 has also been shown to weaken papillary muscle contraction.<a class="elsevierStyleCrossRef" href="#bib0390">24</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>The mechanism(s) of neurologic involvement is poorly understood. Two mechanisms have been postulated, one based on the passive diffusion of cytokines,<a class="elsevierStyleCrossRef" href="#bib0375">21</a> supported by the finding that high levels of IL-6 and IL-15,<a class="elsevierStyleCrossRef" href="#bib0395">25</a> and a second one associated with trafficking of the CAR T cell in the central nervous system,<a class="elsevierStyleCrossRef" href="#bib0375">21</a> as CAR T-cell numbers were found to be significantly higher in cerebral spinal fluid (CSF) in those patients with neurotoxicity,<a class="elsevierStyleCrossRef" href="#bib0395">25</a> although CAR T cells were not detected in the CSF of all patients experiencing neurologic toxicities.<a class="elsevierStyleCrossRef" href="#bib0400">26</a> Disruption of the blood-brain barrier (BBB) may also be a contributory factor,<a class="elsevierStyleCrossRefs" href="#bib0375">21,27</a> failing to protect the CSF from high concentrations of systemic cytokines.<a class="elsevierStyleCrossRef" href="#bib0410">28</a> Of note, neurologic symptoms might occur after the peak of cytokines, especially after CAR T-cell therapy, so some authors consider neurological involvement as a separate entity, named CAR-T-cell-related encephalopathy syndrome (CRES).<a class="elsevierStyleCrossRef" href="#bib0395">25</a> In addition, IL-6 blocking therapy also fails to reverse neurotoxicity in some individuals who are treated for CRS. Whether this is due to limited antibody penetration into the CNS due to the BBB, important roles for other cytokines or cytokine-independent mechanism is unknown.<a class="elsevierStyleCrossRef" href="#bib0415">29</a>Some patients with severe CRS develop a clinical phenotype that resembles hemophagocytic limphohistiocytosis (HLH),<a class="elsevierStyleCrossRefs" href="#bib0315">9,30</a> a life threatening disorder characterized by severe systemic inflammation caused by excessive activation of cytotoxic CD8 T cells, macrophages and histiocytes.<a class="elsevierStyleCrossRef" href="#bib0425">31</a> Primary HLH is caused by mutations in genes involved in cytolitic granule exocytosis, leading to depressed NK function and allowing macrophage activation to occur spontaneously.<a class="elsevierStyleCrossRef" href="#bib0420">30</a> Excessive expression of IL-6 could lead to impaired lytic activity similar to that seen in familial HLH, which results in the excessive activation and expansion of CD8+T cells and macrophages.<a class="elsevierStyleCrossRef" href="#bib0380">22</a>Clinical manifestationsCRS tipically manifest with constitutional symptoms, such as fever, malaise, anorexia, myalgia, headache and nausea, but can affect any organ system including cardiovascular, respiratory, skin, gastrointestinal, hepatic, renal hematological and nervous system. CRS can range in severity from low grade constitutional symptoms to a high-grade syndrome associated with severe multiorgan dysfunction (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0295">5,8,11,25,32,33</a> Several grading scales according to severity have been proposed <a class="elsevierStyleCrossRefs" href="#bib0295">5,10,25,34</a>(<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Fever is a hallmark, ranging 40°C, but some patients develop CRS without fever.<a class="elsevierStyleCrossRef" href="#bib0445">35</a> Respiratory symptoms can range from minimal dyspnea and tachypnea to severe respiratory failure, needing mechanical ventilation.<a class="elsevierStyleCrossRef" href="#bib0295">5</a> CRS-related cardiovascular toxicity can include tachycardia, hypotension, arrhythmias, elevation in serum troponin, prolongation of the corrected QT interval, LV dysfunction and cardiopulmonary arrest.<a class="elsevierStyleCrossRef" href="#bib0385">23</a> Neurologic symptoms and signs including confusion, delirium, aphasia, motor weakness, obtundation, myoclonus, seizure and cerebral edema have been reported.<a class="elsevierStyleCrossRef" href="#bib0375">21</a> Diminished attention, language disturbance and dysgraphia are the earliest signs.<a class="elsevierStyleCrossRef" href="#bib0395">25</a> Although most cases of neurological toxicity are reversible, life-threatening cerebral edema in patients treated with CAR T cells has been reported.<a class="elsevierStyleCrossRef" href="#bib0375">21</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Rarely, patients treated with BiTe <a class="elsevierStyleCrossRefs" href="#bib0425">31,36</a> or CAR T-cells<a class="elsevierStyleCrossRef" href="#bib0455">37</a> and severe CRS can evolve into fulminant HLH.<a class="elsevierStyleCrossRef" href="#bib0395">25</a> This syndrome is characterized by the presence of fever, cytopenias, splenomegaly, hypofibrinogenemia, hyperferritinemia, haemophagocytosis, high levels of soluble CD25 and low NK cell activity, lymphohistiocytic tissue infiltration and multiorgan failure.<a class="elsevierStyleCrossRef" href="#bib0460">38</a>Symptoms of CRS typically occur within 30-120minutes after infusion has been initiated,<a class="elsevierStyleCrossRef" href="#bib0465">39</a> and typically the risk is greater during the first infusion.<a class="elsevierStyleCrossRef" href="#bib0470">40</a> After CAR T-cell therapy, the onset of CRS symptoms seems to be dependent on the administered dose of the active agent of the proliferation kinetics of adoptively transferred cells and ranges from a few minutes up to 14 days but usually occurs within the first week.<a class="elsevierStyleCrossRef" href="#bib0325">11</a>DiagnosticToxicity of these new treatments is distinct from those seen with traditional chemotherapies and we have to be aware for fast recognition. Actually there are no established diagnostic criteria for the CRS. An accurate approach included 3 items: a) compatible clinical symptoms, b) elevated biomarkers and c) recent treatment with any biological agent. As described previously the inflammatory response can manifest with low-grade or high-grade of clinical symptoms. Almost always fever, constitutional symptoms, and can evolve to hypotension, hypoxia and/or neurologic disorders.<a class="elsevierStyleCrossRefs" href="#bib0400">26,33</a> Elevated markers of inflammation such as ferritin or CRP,<a class="elsevierStyleCrossRef" href="#bib0400">26</a> or abnormal laboratory findings indicated organ dysfunction are commonly. The severity will be determined by the intensity of the symptoms and their response to treatment (see <a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Circulating cytokine levels could serve as biomarkers to diagnose and potentially quantify syndrome severity but this are often costly and may not be readily available in all clinical settings. CRP is produced by the liver in response to IL-6 so serve as a reliable surrogate for IL-6 bioactivity.<a class="elsevierStyleCrossRefs" href="#bib0295">5,23,41</a> Moreover is rapid, inexpensive, can be monitoring and available in most hospitals. A combination of clinical features and biomarkers has been employed for predicting severity.<a class="elsevierStyleCrossRef" href="#bib0320">10</a> There are ongoing investigations for determine a cytokine profile for predict severity and guide treatment <a class="elsevierStyleCrossRefs" href="#bib0480">42,43</a> and also for establish CRP peak levels and fold change to identified patients at risk for sCRS.<a class="elsevierStyleCrossRefs" href="#bib0400">26,30</a> High risk patients should be close monitored like patients with high disease burden and comorbidities.The syndrome can be overlapping with other pathologies simultaneously that have to be rule out. Events can appear during or shortly after first exposure to a “new” drug, so a differentiation to anaphylaxis may be difficult. There are few allergy-specific symptoms such as urticaria or glottis edema which may guide an allergic diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0360">18,44</a> In a subset of patients with sCRS there is a symptom pattern similar to that seen in secondary HLH.<a class="elsevierStyleCrossRef" href="#bib0420">30</a> Another clinical differential diagnosis is the drug-induced capillary leak syndrome (CLS), where predominates generalized edema, exudative serous cavity effusions, noncardiogenic pulmonary edema, persistent hypotension in some cases with hipovolemic shock, weight gain and acute kidney injury. Moderate to severe capillary leak syndrome are often indistinguishable from sepsis and septic shock.PreventionTo address safety innovative strategies have been described as dual-receptor mode for engineered T cells, switch molecules for control the dose of activated CAR-T cells or insertion of suicide genes.<a class="elsevierStyleCrossRefs" href="#bib0375">21,45–47</a> Despite a lot of investigation for predicting toxicity no consensus exists on the optimal assay format to test.<a class="elsevierStyleCrossRef" href="#bib0510">48</a> Dose fractionation, reduction of the infusion rate, corticosteroid premedication and close monitoring is the routine practice for increasing safety.TreatmentThere is a systematic approach based on anti-IL6 therapy and corticosteroids. General precautions have been recommended by some authors.<a class="elsevierStyleCrossRefs" href="#bib0395">25,33</a> In our hospital patients remain hospitalized in general ward seven days after received CAR-T cell, and 48h for BiTe therapy. If fever appears is mandatory to assess for infection and start empiric broad-spectrum antibiotic therapy, because undiagnosed infections can have catastrophic consequences.We recommend a four step approach (<a class="elsevierStyleCrossRef" href="#fig0015">figure 3</a>): monitoring, assessment of CRS, grading toxicity and treatment. The management of CRS have to be in accordance with the grade of toxicity. Grade 1 CRS can be managed with symptomatic treatment on the hospitalization ward. In patients with grade 2, CRS hypotension have to be promptly treated with intravenous fluid boluses. If hypotension is refractory to fluid boluses it has to be considered transfer the patient to the ICU and should be initiated anti-IL6 therapy and low-dose vasopressors. It's important that patients treated with CAR-T cell and high risk immunotherapy are managed with a multidisciplinary approach, including intensivist that should be involved from the beginning of these therapies. Bedside echocardiography and/or non-invasive hemodynamic monitoring are recommended for assess LV function.<a class="elsevierStyleCrossRefs" href="#bib0295">5,25</a> Hypoxia could be part of the syndrome and should be managed as needed, even with high flow oxygen or mechanical ventilation. It is necessary to evaluate other organ toxicities. Severe CRS, involving grades 3 and 4, or persistent grade 2 despite two doses of anti-iL6 therapy, should be treated with corticosteroids.<a class="elsevierStyleCrossRefs" href="#bib0395">25,35</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>There is a strong positive correlation with the peak IL-6 levels and the severity of the CRS.<a class="elsevierStyleCrossRefs" href="#bib0310">8,25,26,49</a> The blockage of IL-6 have became the best choice for controlling moderate-severe CRS.<a class="elsevierStyleCrossRefs" href="#bib0295">5,8,26,50</a> Tocilizumab is a MAb blocking IL-6 receptor (IL-6R). First approved for the treatment of rheumatoid arthritis <a class="elsevierStyleCrossRef" href="#bib0525">51</a> and in 2017 for the treatment of severe or life-threatening CAR-T cell induced CRS. The optimal dose and schedule are not well established,<a class="elsevierStyleCrossRef" href="#bib0530">52</a> the normal dose is 8mg/kg (data generated in clinical trials). It is controversial the use of a second dose (in the next 8 to 24h) if the patient does not respond because it has a very long half-life (10-14 days). Tocilizumab has a very secure profile with few adverse effects <a class="elsevierStyleCrossRef" href="#bib0530">52</a> like prolonged neutropenia (probably for margination in the vessel), thrombopenya, elevation of transaminases. Siltuximab is a human-murine chimeric mAb against IL-6 and in 2014 it was FDA-approved for the treatment of multicentric Castleman's disease. Various authors have demonstrated rapid resolution, between 1 to 3 days, of the sCRS after IL-6 blockage. It is important to note that IL-6 blockade does not appear to diminish expansion of the CAR-T cells.<a class="elsevierStyleCrossRefs" href="#bib0315">9,26,35,52</a> Despite this, the current approach aims at limiting the use only for severe and life-threatening CRS because early immunosuppression could limit the efficacy of immunotherapy.<a class="elsevierStyleCrossRef" href="#bib0295">5</a>Corticosteroids are also effective in the management of sCRS, however in the context of immunotherapy should be avoided if it's possible because suppress T-cell function and/or induce T-cell apoptosis. It has to be considered only when anti IL-6 therapy failed.<a class="elsevierStyleCrossRef" href="#bib0395">25</a> Specially in the context of CAR-T cell therapy, because steroids reduce its clinical effectiveness by blocking T-cell activation, function and proliferation,<a class="elsevierStyleCrossRef" href="#bib0530">52</a> and could potentially favour a recurrence of disease.<a class="elsevierStyleCrossRef" href="#bib0400">26</a> Glucocorticoids have been shown to reduce cytokine production secondary to BiTe therapy without compromising cytotoxic T-cell proliferation and cytotoxicity.<a class="elsevierStyleCrossRef" href="#bib0535">53</a> There is not a steroid established dose, in our center we use metilprednisolone 1-2mg/kg/day, other authors referred more elevated doses. The duration of corticosteroid treatment is determined by the resolution or improvement of symptoms.In the onset of CRES treatment changes. Seizure prophylaxis with levetiracetam is recommended for 30 days after infusion if the CAR-T cell therapy has been associated to CRES. Status epilepticus should be managed with benzodiazepines and additional antiepileptics (levetiracetam and phenobarbital are preferred). In severe cases of CRES, seizures, motor weakness, mental obtundation and cerebral edema can occur so we recommend transfer to the ICU for frequent evaluation and monitoring with EEG and make a CT scan or RNM for discard a structural origin of the symptoms. The manifestation of CRES can be biphasic. The first phase occurs with the onset of the CRS within the first 5 days. The second phase occurs beyond 5 days, after the fever and other symptoms of CRS subside, in this case the anti-IL-6 therapy seems to be less effective, and steroids is the preferred treatment (dexamethasone 10mg/6h iv). If there is no improvement or worsening, blockage IL-6 is mandatory because there is a greater permeability of the BBB in the context of CRS enabling increased diffusion of the MAb and effective blocking IL-6.<a class="elsevierStyleCrossRef" href="#bib0395">25</a>Other specific agents against cytokines have been used with limited results such as infliximab or etanercep. In refractory cases methylprednisolone boluses and/or cyclophosphamide for limiting CAR-T cell proliferation could be considered.PrognosisThe global prognosis of CRS is good, more times is mild, often reversible with good response to specific treatment. Nevertheless this syndrome can be severe with life-threatening consequences and rapidly progress to a multiorgan failure. Neurologic impairment can be also reversible, but could be serious, with cerebral oedema and brain death can occur.Another handicap is the poor prognosis of the disease itself. There can exist concerns about the indication of intensive care admission in these patients, but we should consider that we are facing patients with a potentially reversible drug related adverse event, treated with a new drug that could change the prognosis of the disease. We consider that the ICU should remain open to these patients, with the support of a multidisciplinary team involving also of oncologist and haematologist, in order to determine the intensity of treatment.FutureIn the following years there will be an expanded use of immunotherapy in cancer <a class="elsevierStyleCrossRef" href="#bib0505">47</a> and due to the potential complications of these therapies, intensivist are having an important role in the management of those patients. Future studies will help to optimize patient selection, preparation, safety, and management of individuals who received immunotherapy and elucidate if potential long-term concerns as genotoxicity are valid.<a class="elsevierStyleCrossRef" href="#bib0540">54</a>Well defined diagnostic criteria, standardized multidisciplinary treatment and determine cytokines profiles for predict severity and guide treatment are interesting topics to work on.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres1256590" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1164217" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1256589" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1164216" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Pathophysiology" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical manifestations" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Diagnostic" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Prevention" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Treatment" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Prognosis" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Future" ] 13 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of interest" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-11-20" "fechaAceptado" => "2019-01-19" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1164217" "palabras" => array:3 [ 0 => "Cytokine release syndrome" 1 => "Cancer" 2 => "Immunotherapy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1164216" "palabras" => array:3 [ 0 => "Síndrome de liberación de citocinas" 1 => "Cáncer" 2 => "Inmunoterapia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Immunotherapy seeks to harness the power of the immune system to eradicate malignant tissues. Despite impressive therapeutic success, however, it can be accompanied by severe adverse effects such as cytokine release syndrome (CRS). These therapies cause the release of a great amount of cytokines, with IL-6 playing a central role, that can potentially lead to multiple organ dysfunction. The diagnosis is based on the presence of compatible clinical symptoms, elevated biomarkers and recent treatment with a biological agent. Mild cases can be managed through symptomatic treatment and fluids, while more severe episodes may need supportive therapy and specific care with the anti-IL-6 receptor monoclonal antibody tocilizumab. Although corticosteroids are also effective, they suppress T-cell activity, and so should only be considered as second line therapy or in cases of severe neurological involvement, since tocilizumab does not cross the blood-brain barrier. Cytokine release syndrome generally has a good prognosis, often being reversible and with a good response to specific treatment. Despite possible concerns about the admission of such patients (mainly with advanced oncological disease), we consider that the Intensive Care Unit should remain an option, since these individuals present a potentially reversible drug-related adverse event and are being treated with a new drug that could change the prognosis of the disorder. Intensive care medicine will become a key component in the management of the complications of modern cancer therapies, dealing with patients presenting an overactive immune system producing organ dysfunction while also trying to maintain treatment efficacy. This is the new paradigm." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La inmunoterapia potencia el sistema inmunitario para erradicar las células malignas. A pesar de mostrar un importante éxito terapéutico, puede ir acompañada de efectos adversos graves, como el síndrome de liberación de citocinas. Dichas terapias pueden causar la liberación de importantes cantidades de citocinas, siendo IL-6 el mediador principal, e inducir un cuadro de disfunción multiorgánica. El diagnóstico se basa en la presencia de síntomas clínicos compatibles, elevación de biomarcadores y tratamiento reciente con un agente biológico. Los casos leves se pueden manejar con tratamiento sintomático y fluidoterapia, mientras que los episodios graves necesitarán tratamiento de soporte y específico con tocilizumab, un anticuerpo monoclonal anti-receptor de IL-6. Los corticoides, aunque efectivos, suprimen la actividad de las células T, por lo que su uso se considera de segunda línea o en afectación neurológica grave, ya que tocilizumab no cruza la barrera hematoencefálica. A pesar de que puedan existir dudas sobre el ingreso en unidades de críticos de estos pacientes, principalmente con enfermedad avanzada, consideramos que podrían beneficiarse del ingreso en las UCI, ya que se trata de pacientes con un evento adverso potencialmente reversible, recibiendo un nuevo fármaco que podría cambiar el pronóstico de su enfermedad. La medicina intensiva es clave en el manejo de las complicaciones de las nuevas terapias oncológicas, tratando pacientes con un sistema inmunitario excesivamente activado mientras se intenta preservar la eficacia del tratamiento. Este es el nuevo paradigma." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 979 "Ancho" => 2152 "Tamanyo" => 230561 ] ] "descripcion" => array:1 [ "en" => "Pathophysiology of cytokine release syndrome." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1670 "Ancho" => 2168 "Tamanyo" => 232859 ] ] "descripcion" => array:1 [ "en" => "Clinical manifestations of cytokine release syndrome." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1658 "Ancho" => 2189 "Tamanyo" => 452876 ] ] "descripcion" => array:1 [ "en" => "Diagnostic and treatment algorithm." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Immunotherapy \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mechanism of action \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monoclonal antibodies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Target specific tumoral antigen and recruit immune cells and complement, promoting phagocytosis, cytotoxicity and apoptosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bispecific T cell-engaging therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Target CD3 on T cells and a surface antigen on the tumor cells, resulting in cytotoxicity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CAR T cells therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T cells from a patient modified ex vivo by introducing a gene that codes for an CAR that bind specifically to a molecule expressed in tumor cells with a potent cytotoxic response \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Checkpoint inhibitors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monoclonal antibodies that block the PD1/PD-L1 and CTLA4-axis. They do not induce direct cytotoxicity but interfere with the ability of cancer cells to avoid immune system attack. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2149222.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Immunotherapy for cancer." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grading Scale \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grade 1 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grade 2 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grade 3 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grade 4 \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTCAE v5.0 <a class="elsevierStyleCrossRef" href="#bib0440">34</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fever \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypotension responding to fluids,Hypoxia responding to FiO2 <0.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypotension managed with one pressor, Hypoxia requiring FiO2> 0.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Life-threatening consequences \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lee Grading Scale<a class="elsevierStyleCrossRef" href="#bib0295">5</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Symptoms require symptomatic treatment only \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypotension responding to fluids or low-dose pressors or grade 2 organ toxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypotension requiring high dose<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> or multiple pressors, hypoxia requiring FiO2>40% or grade 3 organ toxicity or grade 4 transaminase elevation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Life threatening, requirements for ventilator support or grade 4 organ toxicity (excluding transaminase elevation) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MD Anderson Grading Scale<a class="elsevierStyleCrossRef" href="#bib0395">25</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FeverGrade 1 organ toxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypotension responding to fluids or low-dose pressors or grade 2 organ toxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypotension requiring high dose<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> or multiple pressor<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a>, hypoxia requiring FiO2>40% or grade 3 organ toxicity or grade 4 transaminase elevation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Life threatening, requirements for ventilator support or grade 4 organ toxicity (excluding transaminase elevation) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Penn Grading Scale<a class="elsevierStyleCrossRef" href="#bib0320">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reaction treated with antipyretics, antiemetics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Need for hospitalization Some signs or organ dysfunction (grade 4 LFTs or grade 3 creatinine) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hospitalization required, organ dysfunction including grade 4 LFTs or grade 3 creatinine, hypotension treated with fluids or low dose vasopressors, hypoxia requiring supplemental oxygen, coagulopathy requiring FFP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Life threatening, such as hypotension requiring high-dose** vasopressors, hypoxia requiring mechanical ventilation \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2149221.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "High dose vasopressors: noradrenaline> or=20 mcg/min, dopamine> or=10 mcg/kg/min, adrenaline> or=10 mcg/min, phenylephrine> or=200 mcg/min" ] ] ] "descripcion" => array:1 [ "en" => "CRS grading scales." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Criteria for sCRS \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Persistent fever for more than 3 days \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Two biomarkers elevation (cytokines, RCP, ferritin...) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At least one organ toxicity: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypotension (requiring vasoactive pressor) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypoxia (SpO2 <90% FiO2 0,21) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurologic disorder (including mental status changes, obtundation, seizures) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2149223.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Diagnostic criteria for sCRS." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:54 [ 0 => array:3 [ "identificador" => "bib0275" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "von Bergwelt-Baildon MSl. 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Estadísticas

Review

Cytokine release syndrome. Reviewing a new entity in the intensive care unit

Síndrome de liberación de citocinas. Revisando una nueva enfermedad en la unidad de cuidados intensivos

Alejandra García Rochea, Cándido Díaz Lagaresb,

Autor para correspondencia

c.diaz@vhebron.net

Corresponding author. Passeig de la Vall d́Hebron 119-129. Hospital Universitario Vall d́Hebron. 3ª planta. Servicio de Medicina Intensiva. CP 08035

, Elena Élezc, Ricard Ferrer Rocad

a Intensive Care Department. SODIR Research Group. Vall d́Hebron University Hospital, Barcelona, España

b Intensive Care Department. SODIR Research Group. Vall d́Hebron University Hospital, Barcelona, España

c Medical Oncology Department. VHIO. Vall d́Hebron University Hospital, Barcelona, España

d Intensive Care Department. SODIR Research Group. Vall d́Hebron University Hospital, Barcelona, España

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cancer is a mayor public health problem worldwide&#44; expected to become the leading cause of death in many developed countries&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">1</span></a> In Spain&#44; it is the first cause of death in men and women over forty years&#44; being responsible of 25&#37; of global mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">2</span></a> During the last two decades&#44; mortality has significantly dropped by means of more effective therapies&#44; including immunotherapy&#44; and improvement in supportive therapy&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">3</span></a> reaching a 5 year survival around 50&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Immunotherapy is a type of biological therapy <a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">4</span></a> that seeks to harness the power of the immune system to eradicate malignant tissues&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">5</span></a> while classic chemotherapy work by stopping or slowing the growth of cancer cells&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">6</span></a> which is associated with immunosuppression and infection&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">7</span></a> These new therapies include monoclonal antibodies &#40;MAb&#41;&#44; bispecific T-cell engaging &#40;BiTe&#41; therapy&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">8</span></a> checkpoint inhibitors <a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">7</span></a> and cellular therapies&#44; as chimeric antigen receptor &#40;CAR&#41; T-cells <span class="elsevierStyleSup">9</span> and T-infiltrating lymphocytes &#40;TIL&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Despite showing impressive therapeutic success&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">10</span></a> these therapies are also accompanied by severe and life-threatening adverse effects&#44; as severe cytokine release syndrome &#40;CRS&#41; and autoimmunity&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a> CRS occurs as a result of massive release of cytokines after immunotherapy&#44; while autoimmune occurs when the targeted tumor associated antigen is expressed on non malignant tissue&#44; so-called &#8220;on target&#44; off-tumor toxicity&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">5</span></a> CRS occurs mainly after BiTe and CAR T-cell therapy&#44; with a quite variable incidence&#44; ranging from 2&#37; to 94&#37;&#44; reflecting different prophylactic approaches&#44; variable doses&#44; underreporting and variable CRS definitions&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">10&#44;12&#44;13</span></a> Checkpoint inhibitors despite occasionally related to CRS<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">14</span></a> are mainly associated with autoimmune events&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">7</span></a> Isolated cases of CRS have been related to hematopoietic stem cell transplantation &#40;HSCT&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">15</span></a> and even conventional chemotherapy <a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a> and radiotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">16</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">CRS was first described in 1989&#44; in kidney transplant recipients treated with the anti-CD3 monoclonal antibody OKT3&#44; which typically developed a flu-like syndrome one hour after the first infusion&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">17</span></a> The syndrome became more relevant after 1997&#44; with the approval of rituximab and a myriad of MAb for the treatment of different cancers&#44; many of them also related to the presence of CRS&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">18&#44;19</span></a> Later on&#44; in 2006&#44; a severe CRS &#40;sCRS&#41; was induced in 6 healthy volunteers who received an anti CD28 monoclonal antibody &#40;TGN1412&#41;&#44; requiring ICU admission for respiratory distress and renal failure&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">20</span></a> In recent years&#44; with the appearance of BiTe and cellular therapies&#44; CRS has been increasingly reported&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Over the last two decades&#44; the number of cancer patients requiring ICU care has dramatically increased&#44; with 15&#37; of ICU beds occupied by cancer patients&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">3</span></a> With the extensive use of immunotherapy in cancer&#44; CRS is being increasingly reported&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Thus&#44; intensive care medicine will become a key component in the management of the complications of modern cancer therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a> We will need to face patients with an over-active immune system&#44; inducing severe organ dysfunction&#44; while we try to keep the efficacy of the treatment&#46; That is the new paradigm&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">We performed a review searching In Medline &#40;Pubmed&#41; database using the term &#8220;cytokine release syndrome&#8221; restricted to articles with the selected term present in title or abstract &#91;TiAb&#93;&#46; All articles identified by the search were initially screened for eligibility on title and abstract independently by two reviewers&#46; The references of the selected articles were in turn used to identify additional studies&#46; Any differences were resolved by consensus&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathophysiology</span><p id="par0035" class="elsevierStylePara elsevierViewall">The rising stars in cancer treatment &#40;MAb&#44; BiTe&#44; CAR T-cell&#41; are approaches by which the patient&#769;s immunological self-defense is strengthened in a feasible and effective manner&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">7</span></a> enhancing the power of the immune system to destroy cancer cells&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">5</span></a> which can cause an excessive release of inflammatory cytokines&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">21</span></a> leading to a severe systemic inflammatory response and multiple organ dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">22</span></a> The source of cytokines can be either target cells themselves or immune cells that have been recruited to the tumor site&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">All these therapies&#44; in different ways&#44; cause a significant activation of the immune system&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">10</span></a> including lymphocytes &#40;B cells&#44; T cells and&#47;or natural killer cells&#41; and&#47;or myeloid cells &#40;macrophages&#44; dendritic cells&#44; and monocytes&#41; which lead to release of lymphocyte derived &#40;IFN gamma&#44; IL-6&#44; sIL-2R alpha&#44; sIL-6R&#44; and GM-CSF&#41; and monocyte&#47;macrophage &#40;IL1-receptor antagonist&#44; IL-10&#44; IL-6&#44; IP-10&#44; monokine&#44; IFN alpha&#44; MIP-1 alpha&#44; MIP-1 beta&#44; and sIL6R&#41; cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">21</span></a> IL-6 plays a central role in CRS&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">5</span></a> There is also evidence of vascular endothelial activation and dysfunction that is triggered by IFN-gamma&#44; IL-6 and TNF-alpha&#46; Activated endothelial cells&#44; in turn&#44; produce more IL-6&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">15</span></a> This excessive IL-6 activation leads to vascular leakage as well as activation of the complement and the coagulation cascade&#44; leading to multiple organ dysfunction and disseminated intravascular coagulation&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">11&#44;22</span></a> IL-6 increases the production of vascular endothelial grown factor&#44; which internalizes vascular endothelial cadherin&#44; a mayor structural protein that mediates adhesion of adjacent cells&#44; leading to vascular leakage&#46; The complement is also involved in increasing the permeability on endothelial cells&#44; as IL-6 upregulates C5a receptors on endothelial cells and increases their responsiveness to C5a&#46; IL-6 also induces tissue factor expression on the cell surface of monocytes&#44; triggering coagulation cascade <a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">22</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46; The pathophysiology of left ventricular &#40;LV&#41; dysfunction may be similar to that observed with sepsis induced and stress &#40;Tako-Tsubo&#41; cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">23</span></a> IL-6 has also been shown to weaken papillary muscle contraction&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">24</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The mechanism&#40;s&#41; of neurologic involvement is poorly understood&#46; Two mechanisms have been postulated&#44; one based on the passive diffusion of cytokines&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">21</span></a> supported by the finding that high levels of IL-6 and IL-15&#44;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> and a second one associated with trafficking of the CAR T cell in the central nervous system&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">21</span></a> as CAR T-cell numbers were found to be significantly higher in cerebral spinal fluid &#40;CSF&#41; in those patients with neurotoxicity&#44;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> although CAR T cells were not detected in the CSF of all patients experiencing neurologic toxicities&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">26</span></a> Disruption of the blood-brain barrier &#40;BBB&#41; may also be a contributory factor&#44;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">21&#44;27</span></a> failing to protect the CSF from high concentrations of systemic cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">28</span></a> Of note&#44; neurologic symptoms might occur after the peak of cytokines&#44; especially after CAR T-cell therapy&#44; so some authors consider neurological involvement as a separate entity&#44; named CAR-T-cell-related encephalopathy syndrome &#40;CRES&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> In addition&#44; IL-6 blocking therapy also fails to reverse neurotoxicity in some individuals who are treated for CRS&#46; Whether this is due to limited antibody penetration into the CNS due to the BBB&#44; important roles for other cytokines or cytokine-independent mechanism is unknown&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">29</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Some patients with severe CRS develop a clinical phenotype that resembles hemophagocytic limphohistiocytosis &#40;HLH&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">9&#44;30</span></a> a life threatening disorder characterized by severe systemic inflammation caused by excessive activation of cytotoxic CD8 T cells&#44; macrophages and histiocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">31</span></a> Primary HLH is caused by mutations in genes involved in cytolitic granule exocytosis&#44; leading to depressed NK function and allowing macrophage activation to occur spontaneously&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">30</span></a> Excessive expression of IL-6 could lead to impaired lytic activity similar to that seen in familial HLH&#44; which results in the excessive activation and expansion of CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T cells and macrophages&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical manifestations</span><p id="par0055" class="elsevierStylePara elsevierViewall">CRS tipically manifest with constitutional symptoms&#44; such as fever&#44; malaise&#44; anorexia&#44; myalgia&#44; headache and nausea&#44; but can affect any organ system including cardiovascular&#44; respiratory&#44; skin&#44; gastrointestinal&#44; hepatic&#44; renal hematological and nervous system&#46; CRS can range in severity from low grade constitutional symptoms to a high-grade syndrome associated with severe multiorgan dysfunction &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">5&#44;8&#44;11&#44;25&#44;32&#44;33</span></a> Several grading scales according to severity have been proposed <a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">5&#44;10&#44;25&#44;34</span></a>&#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Fever is a hallmark&#44; ranging 40<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; but some patients develop CRS without fever&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">35</span></a> Respiratory symptoms can range from minimal dyspnea and tachypnea to severe respiratory failure&#44; needing mechanical ventilation&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">5</span></a> CRS-related cardiovascular toxicity can include tachycardia&#44; hypotension&#44; arrhythmias&#44; elevation in serum troponin&#44; prolongation of the corrected QT interval&#44; LV dysfunction and cardiopulmonary arrest&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">23</span></a> Neurologic symptoms and signs including confusion&#44; delirium&#44; aphasia&#44; motor weakness&#44; obtundation&#44; myoclonus&#44; seizure and cerebral edema have been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">21</span></a> Diminished attention&#44; language disturbance and dysgraphia are the earliest signs&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> Although most cases of neurological toxicity are reversible&#44; life-threatening cerebral edema in patients treated with CAR T cells has been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Rarely&#44; patients treated with BiTe <a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">31&#44;36</span></a> or CAR T-cells<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">37</span></a> and severe CRS can evolve into fulminant HLH&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> This syndrome is characterized by the presence of fever&#44; cytopenias&#44; splenomegaly&#44; hypofibrinogenemia&#44; hyperferritinemia&#44; haemophagocytosis&#44; high levels of soluble CD25 and low NK cell activity&#44; lymphohistiocytic tissue infiltration and multiorgan failure&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">38</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Symptoms of CRS typically occur within 30-120<span class="elsevierStyleHsp" style=""></span>minutes after infusion has been initiated&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">39</span></a> and typically the risk is greater during the first infusion&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">40</span></a> After CAR T-cell therapy&#44; the onset of CRS symptoms seems to be dependent on the administered dose of the active agent of the proliferation kinetics of adoptively transferred cells and ranges from a few minutes up to 14 days but usually occurs within the first week&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnostic</span><p id="par0070" class="elsevierStylePara elsevierViewall">Toxicity of these new treatments is distinct from those seen with traditional chemotherapies and we have to be aware for fast recognition&#46; Actually there are no established diagnostic criteria for the CRS&#46; An accurate approach included 3 items&#58; a&#41; compatible clinical symptoms&#44; b&#41; elevated biomarkers and c&#41; recent treatment with any biological agent&#46; As described previously the inflammatory response can manifest with low-grade or high-grade of clinical symptoms&#46; Almost always fever&#44; constitutional symptoms&#44; and can evolve to hypotension&#44; hypoxia and&#47;or neurologic disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">26&#44;33</span></a> Elevated markers of inflammation such as ferritin or CRP&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">26</span></a> or abnormal laboratory findings indicated organ dysfunction are commonly&#46; The severity will be determined by the intensity of the symptoms and their response to treatment &#40;see <a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Circulating cytokine levels could serve as biomarkers to diagnose and potentially quantify syndrome severity but this are often costly and may not be readily available in all clinical settings&#46; CRP is produced by the liver in response to IL-6 so serve as a reliable surrogate for IL-6 bioactivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">5&#44;23&#44;41</span></a> Moreover is rapid&#44; inexpensive&#44; can be monitoring and available in most hospitals&#46; A combination of clinical features and biomarkers has been employed for predicting severity&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">10</span></a> There are ongoing investigations for determine a cytokine profile for predict severity and guide treatment <a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">42&#44;43</span></a> and also for establish CRP peak levels and fold change to identified patients at risk for sCRS&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">26&#44;30</span></a> High risk patients should be close monitored like patients with high disease burden and comorbidities&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The syndrome can be overlapping with other pathologies simultaneously that have to be rule out&#46; Events can appear during or shortly after first exposure to a &#8220;new&#8221; drug&#44; so a differentiation to anaphylaxis may be difficult&#46; There are few allergy-specific symptoms such as urticaria or glottis edema which may guide an allergic diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">18&#44;44</span></a> In a subset of patients with sCRS there is a symptom pattern similar to that seen in secondary HLH&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">30</span></a> Another clinical differential diagnosis is the drug-induced capillary leak syndrome &#40;CLS&#41;&#44; where predominates generalized edema&#44; exudative serous cavity effusions&#44; noncardiogenic pulmonary edema&#44; persistent hypotension in some cases with hipovolemic shock&#44; weight gain and acute kidney injury&#46; Moderate to severe capillary leak syndrome are often indistinguishable from sepsis and septic shock&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Prevention</span><p id="par0085" class="elsevierStylePara elsevierViewall">To address safety innovative strategies have been described as dual-receptor mode for engineered T cells&#44; switch molecules for control the dose of activated CAR-T cells or insertion of suicide genes&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">21&#44;45&#8211;47</span></a> Despite a lot of investigation for predicting toxicity no consensus exists on the optimal assay format to test&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">48</span></a> Dose fractionation&#44; reduction of the infusion rate&#44; corticosteroid premedication and close monitoring is the routine practice for increasing safety&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Treatment</span><p id="par0090" class="elsevierStylePara elsevierViewall">There is a systematic approach based on anti-IL6 therapy and corticosteroids&#46; General precautions have been recommended by some authors&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">25&#44;33</span></a> In our hospital patients remain hospitalized in general ward seven days after received CAR-T cell&#44; and 48<span class="elsevierStyleHsp" style=""></span>h for BiTe therapy&#46; If fever appears is mandatory to assess for infection and start empiric broad-spectrum antibiotic therapy&#44; because undiagnosed infections can have catastrophic consequences&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">We recommend a four step approach &#40;<a class="elsevierStyleCrossRef" href="#fig0015">figure 3</a>&#41;&#58; monitoring&#44; assessment of CRS&#44; grading toxicity and treatment&#46; The management of CRS have to be in accordance with the grade of toxicity&#46; Grade 1 CRS can be managed with symptomatic treatment on the hospitalization ward&#46; In patients with grade 2&#44; CRS hypotension have to be promptly treated with intravenous fluid boluses&#46; If hypotension is refractory to fluid boluses it has to be considered transfer the patient to the ICU and should be initiated anti-IL6 therapy and low-dose vasopressors&#46; It&#39;s important that patients treated with CAR-T cell and high risk immunotherapy are managed with a multidisciplinary approach&#44; including intensivist that should be involved from the beginning of these therapies&#46; Bedside echocardiography and&#47;or non-invasive hemodynamic monitoring are recommended for assess LV function&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">5&#44;25</span></a> Hypoxia could be part of the syndrome and should be managed as needed&#44; even with high flow oxygen or mechanical ventilation&#46; It is necessary to evaluate other organ toxicities&#46; Severe CRS&#44; involving grades 3 and 4&#44; or persistent grade 2 despite two doses of anti-iL6 therapy&#44; should be treated with corticosteroids&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">25&#44;35</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">There is a strong positive correlation with the peak IL-6 levels and the severity of the CRS&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">8&#44;25&#44;26&#44;49</span></a> The blockage of IL-6 have became the best choice for controlling moderate-severe CRS&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">5&#44;8&#44;26&#44;50</span></a> Tocilizumab is a MAb blocking IL-6 receptor &#40;IL-6R&#41;&#46; First approved for the treatment of rheumatoid arthritis <a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">51</span></a> and in 2017 for the treatment of severe or life-threatening CAR-T cell induced CRS&#46; The optimal dose and schedule are not well established&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">52</span></a> the normal dose is 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg &#40;data generated in clinical trials&#41;&#46; It is controversial the use of a second dose &#40;in the next 8 to 24<span class="elsevierStyleHsp" style=""></span>h&#41; if the patient does not respond because it has a very long half-life &#40;10-14 days&#41;&#46; Tocilizumab has a very secure profile with few adverse effects <a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">52</span></a> like prolonged neutropenia &#40;probably for margination in the vessel&#41;&#44; thrombopenya&#44; elevation of transaminases&#46; Siltuximab is a human-murine chimeric mAb against IL-6 and in 2014 it was FDA-approved for the treatment of multicentric Castleman&#39;s disease&#46; Various authors have demonstrated rapid resolution&#44; between 1 to 3 days&#44; of the sCRS after IL-6 blockage&#46; It is important to note that IL-6 blockade does not appear to diminish expansion of the CAR-T cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">9&#44;26&#44;35&#44;52</span></a> Despite this&#44; the current approach aims at limiting the use only for severe and life-threatening CRS because early immunosuppression could limit the efficacy of immunotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">5</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Corticosteroids are also effective in the management of sCRS&#44; however in the context of immunotherapy should be avoided if it&#39;s possible because suppress T-cell function and&#47;or induce T-cell apoptosis&#46; It has to be considered only when anti IL-6 therapy failed&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a> Specially in the context of CAR-T cell therapy&#44; because steroids reduce its clinical effectiveness by blocking T-cell activation&#44; function and proliferation&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">52</span></a> and could potentially favour a recurrence of disease&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">26</span></a> Glucocorticoids have been shown to reduce cytokine production secondary to BiTe therapy without compromising cytotoxic T-cell proliferation and cytotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">53</span></a> There is not a steroid established dose&#44; in our center we use metilprednisolone 1-2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; other authors referred more elevated doses&#46; The duration of corticosteroid treatment is determined by the resolution or improvement of symptoms&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In the onset of CRES treatment changes&#46; Seizure prophylaxis with levetiracetam is recommended for 30 days after infusion if the CAR-T cell therapy has been associated to CRES&#46; Status epilepticus should be managed with benzodiazepines and additional antiepileptics &#40;levetiracetam and phenobarbital are preferred&#41;&#46; In severe cases of CRES&#44; seizures&#44; motor weakness&#44; mental obtundation and cerebral edema can occur so we recommend transfer to the ICU for frequent evaluation and monitoring with EEG and make a CT scan or RNM for discard a structural origin of the symptoms&#46; The manifestation of CRES can be biphasic&#46; The first phase occurs with the onset of the CRS within the first 5 days&#46; The second phase occurs beyond 5 days&#44; after the fever and other symptoms of CRS subside&#44; in this case the anti-IL-6 therapy seems to be less effective&#44; and steroids is the preferred treatment &#40;dexamethasone 10<span class="elsevierStyleHsp" style=""></span>mg&#47;6<span class="elsevierStyleHsp" style=""></span>h iv&#41;&#46; If there is no improvement or worsening&#44; blockage IL-6 is mandatory because there is a greater permeability of the BBB in the context of CRS enabling increased diffusion of the MAb and effective blocking IL-6&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Other specific agents against cytokines have been used with limited results such as infliximab or etanercep&#46; In refractory cases methylprednisolone boluses and&#47;or cyclophosphamide for limiting CAR-T cell proliferation could be considered&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Prognosis</span><p id="par0120" class="elsevierStylePara elsevierViewall">The global prognosis of CRS is good&#44; more times is mild&#44; often reversible with good response to specific treatment&#46; Nevertheless this syndrome can be severe with life-threatening consequences and rapidly progress to a multiorgan failure&#46; Neurologic impairment can be also reversible&#44; but could be serious&#44; with cerebral oedema and brain death can occur&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Another handicap is the poor prognosis of the disease itself&#46; There can exist concerns about the indication of intensive care admission in these patients&#44; but we should consider that we are facing patients with a potentially reversible drug related adverse event&#44; treated with a new drug that could change the prognosis of the disease&#46; We consider that the ICU should remain open to these patients&#44; with the support of a multidisciplinary team involving also of oncologist and haematologist&#44; in order to determine the intensity of treatment&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Future</span><p id="par0130" class="elsevierStylePara elsevierViewall">In the following years there will be an expanded use of immunotherapy in cancer <a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">47</span></a> and due to the potential complications of these therapies&#44; intensivist are having an important role in the management of those patients&#46; Future studies will help to optimize patient selection&#44; preparation&#44; safety&#44; and management of individuals who received immunotherapy and elucidate if potential long-term concerns as genotoxicity are valid&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">54</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Well defined diagnostic criteria&#44; standardized multidisciplinary treatment and determine cytokines profiles for predict severity and guide treatment are interesting topics to work on&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Immunotherapy seeks to harness the power of the immune system to eradicate malignant tissues&#46; Despite impressive therapeutic success&#44; however&#44; it can be accompanied by severe adverse effects such as cytokine release syndrome &#40;CRS&#41;&#46; These therapies cause the release of a great amount of cytokines&#44; with IL-6 playing a central role&#44; that can potentially lead to multiple organ dysfunction&#46; The diagnosis is based on the presence of compatible clinical symptoms&#44; elevated biomarkers and recent treatment with a biological agent&#46; Mild cases can be managed through symptomatic treatment and fluids&#44; while more severe episodes may need supportive therapy and specific care with the anti-IL-6 receptor monoclonal antibody tocilizumab&#46; Although corticosteroids are also effective&#44; they suppress T-cell activity&#44; and so should only be considered as second line therapy or in cases of severe neurological involvement&#44; since tocilizumab does not cross the blood-brain barrier&#46; Cytokine release syndrome generally has a good prognosis&#44; often being reversible and with a good response to specific treatment&#46; Despite possible concerns about the admission of such patients &#40;mainly with advanced oncological disease&#41;&#44; we consider that the Intensive Care Unit should remain an option&#44; since these individuals present a potentially reversible drug-related adverse event and are being treated with a new drug that could change the prognosis of the disorder&#46; Intensive care medicine will become a key component in the management of the complications of modern cancer therapies&#44; dealing with patients presenting an overactive immune system producing organ dysfunction while also trying to maintain treatment efficacy&#46; This is the new paradigm&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La inmunoterapia potencia el sistema inmunitario para erradicar las c&#233;lulas malignas&#46; A pesar de mostrar un importante &#233;xito terap&#233;utico&#44; puede ir acompa&#241;ada de efectos adversos graves&#44; como el s&#237;ndrome de liberaci&#243;n de citocinas&#46; Dichas terapias pueden causar la liberaci&#243;n de importantes cantidades de citocinas&#44; siendo IL-6 el mediador principal&#44; e inducir un cuadro de disfunci&#243;n multiorg&#225;nica&#46; El diagn&#243;stico se basa en la presencia de s&#237;ntomas cl&#237;nicos compatibles&#44; elevaci&#243;n de biomarcadores y tratamiento reciente con un agente biol&#243;gico&#46; Los casos leves se pueden manejar con tratamiento sintom&#225;tico y fluidoterapia&#44; mientras que los episodios graves necesitar&#225;n tratamiento de soporte y espec&#237;fico con tocilizumab&#44; un anticuerpo monoclonal anti-receptor de IL-6&#46; Los corticoides&#44; aunque efectivos&#44; suprimen la actividad de las c&#233;lulas T&#44; por lo que su uso se considera de segunda l&#237;nea o en afectaci&#243;n neurol&#243;gica grave&#44; ya que tocilizumab no cruza la barrera hematoencef&#225;lica&#46; A pesar de que puedan existir dudas sobre el ingreso en unidades de cr&#237;ticos de estos pacientes&#44; principalmente con enfermedad avanzada&#44; consideramos que podr&#237;an beneficiarse del ingreso en las UCI&#44; ya que se trata de pacientes con un evento adverso potencialmente reversible&#44; recibiendo un nuevo f&#225;rmaco que podr&#237;a cambiar el pron&#243;stico de su enfermedad&#46; La medicina intensiva es clave en el manejo de las complicaciones de las nuevas terapias oncol&#243;gicas&#44; tratando pacientes con un sistema inmunitario excesivamente activado mientras se intenta preservar la eficacia del tratamiento&#46; Este es el nuevo paradigma&#46;</p></span>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Immunotherapy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mechanism of action&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Monoclonal antibodies&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Target specific tumoral antigen and recruit immune cells and complement&#44; promoting phagocytosis&#44; cytotoxicity and apoptosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bispecific T cell-engaging therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Target CD3 on T cells and a surface antigen on the tumor cells&#44; resulting in cytotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CAR T cells therapy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T cells from a patient modified ex vivo by introducing a gene that codes for an CAR that bind specifically to a molecule expressed in tumor cells with a potent cytotoxic response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Checkpoint inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Monoclonal antibodies that block the PD1&#47;PD-L1 and CTLA4-axis&#46; They do not induce direct cytotoxicity but interfere with the ability of cancer cells to avoid immune system attack&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grade 3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Grade 4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">CTCAE v5&#46;0 <a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Hypotension responding to fluids&#44;Hypoxia responding to FiO2 &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Hypotension managed with one pressor&#44; Hypoxia requiring FiO2<span class="elsevierStyleHsp" style=""></span>&#62; 0&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Life-threatening consequences&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Lee Grading Scale<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">5</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Symptoms require symptomatic treatment only&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Hypotension responding to fluids or low-dose pressors or grade 2 organ toxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Hypotension requiring high dose<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a> or multiple pressors&#44; hypoxia requiring FiO2<span class="elsevierStyleHsp" style=""></span>&#62;40&#37; or grade 3 organ toxicity or grade 4 transaminase elevation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Life threatening&#44; requirements for ventilator support or grade 4 organ toxicity &#40;excluding transaminase elevation&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">MD Anderson Grading Scale<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">FeverGrade 1 organ toxicity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Hypotension responding to fluids or low-dose pressors or grade 2 organ toxicity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Hypotension requiring high dose<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a> or multiple pressor<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>&#44; hypoxia requiring FiO2<span class="elsevierStyleHsp" style=""></span>&#62;40&#37; or grade 3 organ toxicity or grade 4 transaminase elevation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Penn Grading Scale<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Hospitalization required&#44; organ dysfunction including grade 4 LFTs or grade 3 creatinine&#44; hypotension treated with fluids or low dose vasopressors&#44; hypoxia requiring supplemental oxygen&#44; coagulopathy requiring FFP&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Two biomarkers elevation &#40;cytokines&#44; RCP&#44; ferritin&#46;&#46;&#46;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">At least one organ toxicity&#58;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Hypotension &#40;requiring vasoactive pressor&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Hypoxia &#40;SpO2 &#60;<span class="elsevierStyleHsp" style=""></span>90&#37; FiO2 0&#44;21&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Neurologic disorder &#40;including mental status changes&#44; obtundation&#44; seizures&#41;&nbsp;\t\t\t\t\t\t\n
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "von Bergwelt-Baildon MSl&#46; Critical Care of Patients With Cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Shimabukuro-Vornhagen"
                            1 => "B&#46; B&#246;ll"
                            2 => "M&#46; Kochaneck"
                            3 => "E&#46; Azoulay"
                          ]
                        ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3322/caac.21351"
                      "Revista" => array:2 [
                        "tituloSerie" => "CA Cancer J Clin"
                        "fecha" => "2016"
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                  ]
                ]
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              "etiqueta" => "2"
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                0 => array:1 [
                  "referenciaCompleta" => "https&#58;&#47;&#47;www&#46;msssi&#46;gob&#46;es&#47;ciudadanos&#47;enfLesiones&#47;enfNoTransmisibles&#47;docs&#47;situacionCancer&#46;pdf&#46; Accessed 13&#46;10&#46;2018&#46;"
                ]
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            2 => array:3 [
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Azoulay"
                            1 => "P&#46; Schellongowski"
                            2 => "M&#46; Darmon"
                            3 => "P&#46;R&#46; Bauer"
                            4 => "D&#46; Benoit"
                            5 => "P&#46; Depuydt"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00134-017-4757-5"
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                        "fecha" => "2017"
                        "volumen" => "43"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28289812"
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              "identificador" => "bib0290"
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                0 => array:1 [
                  "referenciaCompleta" => "https&#58;&#47;&#47;www&#46;cancer&#46;gov&#47;about-cancer&#47;treatment&#47;types&#47;immunotherapy&#46; Accessed 13&#46;10&#46;2018&#46;"
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              ]
            ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Current concepts in the diagnosis and management of cytokine release syndrome"
                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;W&#46; Lee"
                            1 => "R&#46; Gardner"
                            2 => "D&#46;L&#46; Porter"
                            3 => "C&#46;U&#46; Louis"
                            4 => "N&#46; Ahmed"
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                    0 => array:2 [
                      "doi" => "10.1182/blood-2014-05-552729"
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                0 => array:1 [
                  "referenciaCompleta" => "https&#58;&#47;&#47;www&#46;cancer&#46;gov&#47;about-cancer&#47;treatment&#47;types&#47;chemotherapy&#35;1&#46; Accessed 13&#46;10&#46;2018&#46;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New drugs&#44; new toxicities&#58; severe side effects of modern targeted and immunotherapy of cancer and their management"
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                          "etal" => true
                          "autores" => array:6 [
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                    0 => array:2 [
                      "doi" => "10.1186/s13054-017-1678-1"
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                  "referenciaCompleta" => "Maude S&#44; Barrett D&#44; Teachey D&#44; Grupp SA&#46; Managing Cytokine Release Syndrome Associated With Novel T Cell-Engaging Therapies&#46; Cancer J 2014&#59; 20&#58; 119-22&#46; 10&#46;1097&#47;PPO&#46; 0000000000000035&#46;"
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                      "titulo" => "Chimeric antigen receptor &#8211;modified T cells for acute lymphoid leukemia"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;A&#46; Grupp"
                            1 => "M&#46; Kalos"
                            2 => "D&#46; Barrett"
                            3 => "R&#46; Aplenc"
                            4 => "D&#46;L&#46; Porter"
                            5 => "S&#46;R&#46; Rheingold"
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1215134"
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                      "titulo" => "Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel"
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                          "etal" => false
                          "autores" => array:5 [
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                      "doi" => "10.1186/s13045-018-0571-y"
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                      "titulo" => "Understanding cytokine release syndrome"
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                          "autores" => array:3 [
                            0 => "P&#46; G&#246;del"
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                    0 => array:2 [
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                        "paginaInicial" => "3312"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                          "etal" => false
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                    0 => array:1 [
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                      "titulo" => "Severe cytokine release syndrome in a patient receiving PD-1- directed therapy"
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                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46; Rotz"
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                            2 => "S&#46; Szabo"
                            3 => "J&#46;L&#46; Mangino"
                            4 => "B&#46;K&#46; Turpin"
                            5 => "J&#46;G&#46; Pressey"
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Información del artículo

ISSN: 02105691
Idioma original: Inglés

DOI:10.1016/j.medin.2019.01.009

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año/Mes	Html	Pdf	Total

2024 Noviembre	28	21	49
2024 Octubre	233	107	340
2024 Septiembre	329	118	447
2024 Agosto	284	97	381
2024 Julio	259	88	347
2024 Junio	261	121	382
2024 Mayo	254	105	359
2024 Abril	215	80	295
2024 Marzo	205	74	279
2024 Febrero	203	90	293
2024 Enero	315	92	407
2023 Diciembre	330	113	443
2023 Noviembre	334	119	453
2023 Octubre	346	122	468
2023 Septiembre	208	103	311
2023 Agosto	136	83	219
2023 Julio	165	72	237
2023 Junio	137	60	197
2023 Mayo	164	91	255
2023 Abril	228	68	296
2023 Marzo	301	103	404
2023 Febrero	289	109	398
2023 Enero	253	102	355
2022 Diciembre	249	87	336
2022 Noviembre	203	100	303
2022 Octubre	238	78	316
2022 Septiembre	180	70	250
2022 Agosto	169	90	259
2022 Julio	172	59	231
2022 Junio	137	57	194
2022 Mayo	228	52	280
2022 Abril	165	68	233
2022 Marzo	212	112	324
2022 Febrero	199	68	267
2022 Enero	289	87	376
2021 Diciembre	232	79	311
2021 Noviembre	203	86	289
2021 Octubre	209	120	329
2021 Septiembre	132	79	211
2021 Agosto	186	106	292
2021 Julio	145	62	207
2021 Junio	175	74	249
2021 Mayo	242	102	344
2021 Abril	559	216	775
2021 Marzo	495	126	621
2021 Febrero	501	113	614
2021 Enero	351	109	460
2020 Diciembre	280	73	353
2020 Noviembre	236	85	321
2020 Octubre	100	22	122
2020 Agosto	1	2	3
2020 Julio	322	73	395
2020 Junio	1103	154	1257
2020 Mayo	632	245	877
2020 Abril	691	338	1029
2020 Marzo	243	61	304
2020 Febrero	172	38	210
2020 Enero	7	5	12
2019 Diciembre	13	14	27
2019 Noviembre	34	31	65
2019 Octubre	21	20	41
2019 Septiembre	4	4	8
2019 Agosto	1	2	3
2019 Junio	18	10	28
2019 Mayo	3	4	7
2019 Abril	6	7	13
2019 Marzo	183	19	202

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