Multimodal Therapeutic Approach of Cytokine Release Syndrome Developing in a Child Given Chimeric Antigen Receptor-Modified T Cell Infusion
Gabriella BottariPietro MerliIsabella GuzzoFrancesca StoppaAnnalisa RuggeriMatteo Di NardoFrancesca Del BufaloFederica GalavernaCorrado CecchettiFranco Locatelli
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Abstract:
Objectives: To describe a pediatric case of cytokine release syndrome secondary to chimeric antigen receptor-modified T cells associated with acute respiratory distress syndrome. Design: Case report. Setting: PICU. Patients: A 14-year-old boy with refractory B cell precursor acute lymphoblastic leukemia given chimeric antigen receptor cells developed severe cytokine release syndrome 7 days after the drug product infusion with progressive respiratory failure. He was admitted to PICU with a clinical picture of acute respiratory distress syndrome, requiring mechanical ventilation, and secondary hemophagocytic lymphohistiocytosis. Interventions: Hemoadsorption with cartridge column (Cytosorb) in combination with continuous renal replacement therapy was associated to the anti-cytokine therapy (tocilizumab, a monoclonal antibody targeting interleukin-6 receptor). Measurements and Main Results: Decrease of the inflammatory biomarkers (ferritin, interleukin-6, interleukin-10) in the first 96 hours associated with a progressive improvement of acute respiratory distress syndrome (Pa o 2 /F io 2 ratio) 7 day after the start of the multimodal treatment. Conclusions: This case suggests that hemoadsorption with cartridge column in combination with continuous renal replacement therapy and tocilizumab is safe and potentially effective in pediatric patients with severe cytokine release syndrome.Keywords:
Cytokine Release Syndrome
Tocilizumab
Cytokine Storm
Macrophage Activation Syndrome
Tocilizumab (TCZ) is the first FDA- approved treatment for systemic juvenile idiopathic arthritis (sJIA). We report 3 cases of cytopenias in children with sJIA treated with TCZ. Two of the children who developed significant cytopenias shortly after initiation of TCZ had a history of macrophage activation syndrome. We raise the possibility that patients with a tendency towards MAS have an increased risk of developing cytopenias when treated with tocilizumab.
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Therapeutic Role of Tocilizumab in SARS-CoV-2-Induced Cytokine Storm: Rationale and Current Evidence
Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab’s therapeutic effects in patients with life-threatening SARS-CoV-2 infection.
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We read with great interest the comment published by Andrianopoulos et al1 in which the authors advocate for cautious use of tocilizumab in coronavirus disease-2019 (COVID-19) patients. Tocilizumab is a monoclonal antibody against the interleukin-6 (IL-6) receptor that has immunosuppressive properties. Whereas accumulating results from uncontrolled trials present tocilizumab as an effective agent blocker of disease progression, some contrasting studies also progressively appear in COVID-19 literature.2-5 This muddies the waters and makes the situation more confused. Therefore, we would like to reinforce the purpose of Andrianopoulos et al1 by commenting on the cytokine storm proposed in COVID-19 as it constituted the rationale for most tocilizumab trials. To this end, we referred to recent articles regarding the two main clinical conditions traditionally linked with the term "cytokine storm," that is, septic shock and cytokine release syndrome (CRS) after CAR-T cells infusion to compare mean/median plasmatic IL-6 levels in these contexts and in COVID-19 patients. Results are presented in Figure 1. The majority of median COVID-19 IL-6 values are far lower than those seen in septic shock or CRS (P < .0002, analysis of variance). In agreement, a recent meta-analysis of IL-6 values in 1426 COVID-19 patients reported mean IL-6 values at 57 pg/mL in severe patients and 17 pg/mL in less severe patients.6 Although clearly elevated above normal range (generally <10 pg/mL depending on kits providers); those values remain far lower from those seen in usual clinical contexts associated with cytokine storms. Actually, despite rare extreme values, these mean concentrations are similar to those described in various inflammatory diseases (chronic infections, Crohn's disease, rheumatoid arthritis, and multiple sclerosis) which are not usually characterized or defined by the occurrence of cytokine storm.7 Of note, by recent international definition, severe COVID-19 can be classified as a viral sepsis,8 that is, organ failure (acute respiratory distress syndrome) induced by a dysregulated response to an infection (SARS-CoV-2). In sepsis, on a general basis, anti-inflammatory strategies did not show any significant efficacy despite numerous clinical trials.9 With that said, one study identified a protective effect of immunomodulatory treatment in a subgroup of septic patients when stratified based on circulating IL-6 values. In this study, the threshold to highlight this effect was 1000 pg/mL.10 In conclusion, it is unquestionable that COVID-19 presents with inflammatory characteristics. As such, there is likely a room for tocilizumab (or other anti-inflammatory drugs) in subgroups of patients to avoid progression toward uncontrolled inflammation. That given, we suggest that such treatment should be envisaged in a more individualized manner and on short period not to amplify marked immunosuppression observed in intensive care unit COVID-19 patients.11, 12 We thus agree with Andrianopoulos et al1 to cautiously consider tocilizumab depending on disease chronology, occurrence of ARDS, IL-6 level stratification and most importantly, the depth of lymphopenia. The authors declare that there are no conflict of interests.
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Younger patients with COVID-19 may experience an exaggerated immune response to SARS-CoV-2 infection and develop cytokine release syndrome (CRS), which may be life threatening. There is no proven antiviral therapy for COVID-19 so far, but profound immunosuppression has recently been suggested as a treatment for COVID-19-associated CRS. We present a case of life-threatening CRS caused by COVID-19 infection with a favourable response to immunosuppressive therapy with tocilizumab (TCZ). The rapid clinical and biochemical improvement following TCZ administration suggests that treatment with immunotherapy can be life-saving in selected patients with COVID-19-induced CRS.
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To date, severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has infected millions of individuals worldwide. This virus causes coronavirus disease 2019 (COVID-19) and has led to numerous deaths worldwide. A large percentage of infected patients present asymptomatically, augmenting the spread of the virus. Symptomatic COVID-19 commonly causes mild to severe respiratory disease and fever, but some individuals experience serious complications resulting in death. Immune compromised, high risk, and elderly individuals are at an increased risk of more severe consequences of the illness such as respiratory failure, organ dysfunction, and shock. Cytokine storm (also known as cytokine release syndrome (CRS)), a systemic inflammatory response that can be triggered by an infection, has been associated with the symptom progression of COVID-19. This review evaluates several published studies that have implemented tocilizumab (TCZ), an IL-6 receptor antibody (US20120253016A1), in COVID-19 treatment. Outcomes and biomarkers of patients treated with TCZ are compared to patients treated with standard of care regimens. Interleukin-6 (IL-6), a prominent inflammatory cytokine involved in CRS in various inflammatory conditions, may have a vital role in the underlying mechanism involved in debilitating SARS-CoV-2 infections and could serve as a viable treatment target. Studies suggest that TCZ may aid in the recovery of patients with COVID-19 and reduce mortality.
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Severe COVID-19 associated pneumonia and acute respiratory distress syndrome has recently been described with life-threatening features of cytokine storm and loosely referred to as hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). Although a recent report indicated favorable responses to the interleukin-1 receptor antagonist, anakinra in eight patients with COVID-19 secondary HLH diagnosed using the HScore calculation, others have suggested that the diagnosis of secondary HLH is uncommon and that the use of the HScore has limited value in guiding immunomodulatory therapy for COVID-19. Here, we provide additional perspective on this important controversy based upon comparisons between 14 COVID-19 cytokine storm patients and 10 secondary HLH patients seen immediately prior to the pandemic. We hypothesize that identification of HLH may relate to the severity or timing of cytokine release and suggest distinguishing between cytokine release syndrome and secondary HLH, reserving the latter term for cases fulfilling diagnostic criteria.
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The in-hospital mortality in patients with COVID-19 could be correlated with severe acute respiratory syndrome coronavirus-2 induced hyper-inflammation, which is attributed to an unconstrained inflammatory cytokine storm. The pro-inflammatory cytokine, specifically, interleukin-6 plays a prominent role in the cytokine storm and may result in alveolar-capillary blood-gas exchange dysfunction. Therefore, the method to block the signal transduction pathway of interleukin-6 could be a potential treatment for severe COVID-19 patients. In this case series of three patients with severe COVID-19, we focus on the rationale for utilization of tocilizumab, an anti-interleukin-6 receptor antibody, which could block the signal transduction pathway of interleukin-6. The observations from this study allowed us to hypothesize that the infusions of tocilizumab may not reduce the elevated level of interleukin-6, and hence may not be a significant therapeutic for reducing in-hospital mortality associated with COVID-19. Additionally, it could also be speculated that interleukin-6 may not be a potentially actionable target cytokine to treat COVID-19-associated cytokine storms.
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Systemic juvenile idiopathic arthritis (sjia) is a chronic inflammatory disease characterized by prolonged systemic and synovial inflammation. Life-threatening complication of sjia is the macrophage activation syndrome (MAS). Tocilizumab (TCZ) is highly effective in children with sjia. However, MAS remains under the treatment of TCZ.
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