For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
27
views
69
references
 Top references
cited by
38
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      198
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: not found

      Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper

      review-article
      Author(s): 1 , 2 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 3 , 4 , , 1 , 2
      Publication date (Electronic):
      Journal: Infection
      Publisher: Springer Berlin Heidelberg
      Keywords: Chimeric antigen receptor, Diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, Bacterial infections, Viral infections, Fungal infections

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignancies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CAR-T constructs are in research for both hematological and non-hematological diseases. Most of the patients receiving CAR-T therapy will develop fever at some point after infusion, mainly due to cytokine release syndrome (CRS). The onset of CRS is often indistinguishable from an infection, which makes management of these patients challenging. In addition to the lymphodepleting chemotherapy and CAR T cells, the treatment of complications with corticosteroids and/or tocilizumab increases the risk of infection in these patients. Data regarding incidence, risk factors and prevention of infections in patients receiving CAR-T cell therapy are scarce. To assist in patient care, a multidisciplinary team from hospitals designated by the Spanish Ministry of Health to perform CAR-T therapy prepared these recommendations. We reviewed the literature on the incidence, risk factors, and management of infections in adult and pediatric patients receiving CAR-T cell treatment. Recommendations cover different areas: monitoring and treatment of hypogammaglobulinemia, prevention, prophylaxis, and management of bacterial, viral, and fungal infections as well as vaccination prior and after CAR-T cell therapy.

          Related collections

          Most cited references69

          • Record: found
          • Abstract: found
          • Article: not found

          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Chaolin Huang, Yeming Wang, Xingwang Li … (2020)
          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
          Article 0 comments Cited 22052 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal

            Hasan K Siddiqi, Mandeep R. Mehra (2020)
            The onslaught of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated coronavirus disease 2019 (COVID-19) has gripped the world in a pandemic and challenged the culture, economy and healthcare infrastructure of its population. It has become increasingly important that health systems and their clinicians adopt a universal consolidated framework to recognize the staged progression of COVID-19 illness in order to deploy and investigate targeted therapy likely to save lives. The largest report of COVID-19 from the Chinese Centers for Disease Control and Prevention summarized findings from 72, 314 cases and noted that while 81% were of a mild nature with an overall case fatality rate of 2.3%, a small sub-group of 5% presented with respiratory failure, septic shock and multi-organ dysfunction resulting in fatality in half of such cases, a finding that suggests that it is within this group that the opportunity for life saving measures may be most pertinent. 1 Once the disease is manifest, supportive measures are initiated with quarantines; however a systematic disease modifying therapeutic approach remains empirical. Pharmacotherapy targeted against the virus holds the greatest promise when applied early in the course of the illness, but its usefulness in advanced stages may be doubtful. 2 , 3 Similarly, use of anti-inflammatory therapy applied too early may not be necessary and could even provoke viral replication such as in the case of corticosteroids. 4 It appears that there are two distinct but overlapping pathological subsets, the first triggered by the virus itself and the second, the host response. Whether in native state, immunoquiescent state as in the elderly, or immunosuppressed state as in heart transplantation, the disease tends to present and follow these two phases, albeit in different levels of severity. The early reports in heart transplantation suggest that symptom expression during the phase of establishment of infection are similar to non-immunosuppressed individuals; however, in limited series the second wave determined by the host-inflammatory response appears to be milder, possibly due to the concomitant use of immuno-modulatory drugs. 5 , 6 Similarly, an epidemiological study from Wuhan in a cohort of 87 patients suggests that precautionary measures of social distancing, sanitization and general hygiene allow heart transplant recipients to experience a low rate of COVID-19 illness. 7 We do not of course, know if they are asymptomatic carriers, since in this survey-based study universal testing during the early 3 months was not employed. One interesting fact in this study was that many heart transplant recipients have hematological changes of lymphopenia due to the effects of immunosuppressive therapy which may obfuscate the laboratory interpretation of infection in such patients should they get infected. Much confusion abounds in the therapeutic tactics employed in COVID-19. It is imperative that a structured approach to clinical phenotyping be undertaken to distinguish the phase where the viral pathogenicity is dominant versus when the host inflammatory response overtakes the pathology. In this editorial we propose a clinical staging system to establish a standardized nomenclature for uniform evaluation and reporting of this disease, to facilitate therapeutic application and evaluate response. We propose the use of a 3-stage classification system, recognizing that COVID-19 illness exhibits three grades of increasing severity which correspond with distinct clinical findings, response to therapy and clinical outcome (Figure ). Figure 1 Classification of COVID-19 Disease States and Potential Therapeutic Targets Figure 1 The figure shows 3 escalating phases of disease progression with COVID-19, with associated signs, symptoms and potential phase-specific therapies. ARDS = Acute respiratory distress syndrome; CRP = C-reactive protein; IL = Interleukin; JAK = Janus Kinase; LDH=Lactate DeHydrogenase; SIRS = Systemic inflammatory response syndrome. Stage I (mild) – Early Infection The initial stage occurs at the time of inoculation and early establishment of disease. For most people, this involves an incubation period associated with mild and often non-specific symptoms such as malaise, fever and a dry cough. During this period, SARS-CoV-2 multiplies and establishes residence in the host, primarily focusing on the respiratory system. Similar to its older relative, SARS-CoV (responsible for the 2002-2003 SARS outbreak), SARS-CoV-2 binds to its target using the angiotensin-converting enzyme 2 (ACE2) receptor on human cells. 8 These receptors are abundantly present on human lung and small intestine epithelium, as well as the vascular endothelium. As a result of the airborne method of transmission as well as affinity for pulmonary ACE2 receptors, the infection usually presents with mild respiratory and systemic symptoms. Diagnosis at this stage includes respiratory sample PCR, serum testing for SARS-CoV-2 IgG and IgM, along with chest imaging, complete blood count (CBC) and liver function tests. CBC may reveal a lymphopenia and neutrophilia without other significant abnormalities. Treatment at this stage is primarily targeted towards symptomatic relief. Should a viable anti-viral therapy (such as remdesivir) be proven beneficial, targeting selected patients during this stage may reduce duration of symptoms, minimize contagiousness and prevent progression of severity. In patients who can keep the virus limited to this stage of COVID-19, prognosis and recovery is excellent. Stage II (moderate) - Pulmonary Involvement (IIa) without and (IIb) with hypoxia In the second stage of established pulmonary disease, viral multiplication and localized inflammation in the lung is the norm. During this stage, patients develop a viral pneumonia, with cough, fever and possibly hypoxia (defined as a PaO2/FiO2 of <300 mmHg). Imaging with chest roentgenogram or computerized tomography reveals bilateral infiltrates or ground glass opacities. Blood tests reveal increasing lymphopenia, along with transaminitis. Markers of systemic inflammation may be elevated, but not remarkably so. It is at this stage that most patients with COVID-19 would need to be hospitalized for close observation and management. Treatment would primarily consist of supportive measures and available anti-viral therapies such as remdesivir (available under compassionate and trial use). It should be noted that serum procalcitonin is low to normal in most cases of COVID-19 pneumonia. In early stage II (without significant hypoxia), the use of corticosteroids in patients with COVID-19 may be avoided. 4 However, if hypoxia ensues, it is likely that patients will progress to requiring mechanical ventilation and in that situation, we believe that use of anti-inflammatory therapy such as with corticosteroids may be useful and can be judiciously employed. Thus, Stage II disease should be subdivided into Stage IIa (without hypoxia) and Stage IIb (with hypoxia). Stage III (severe) – Systemic Hyperinflammation A minority of COVID-19 patients will transition into the third and most severe stage of illness, which manifests as an extra-pulmonary systemic hyperinflammation syndrome. In this stage, markers of systemic inflammation appear to be elevated. COVID-19 infection results in a decrease in helper, suppressor and regulatory T cell counts. 9 Studies have shown that inflammatory cytokines and biomarkers such as interleukin (IL)-2, IL-6, IL-7, granulocyte-colony stimulating factor, macrophage inflammatory protein 1-α, tumor necrosis factor-α, C-reactive protein, ferritin, and D-dimer are significantly elevated in those patients with more severe disease. 10 Troponin and N-terminal pro B-type natriuretic peptide (NT-proBNP) can also be elevated. A form akin to hemophagocytic lymphohistiocytosis (sHLH) may occur in patients in this advanced stage of disease. 11 In this stage, shock, vasoplegia, respiratory failure and even cardiopulmonary collapse are discernable. Systemic organ involvement, even myocarditis, would manifest during this stage. Tailored therapy in stage III hinges on the use of immunomodulatory agents to reduce systemic inflammation before it overwhelmingly results in multi-organ dysfunction. In this phase, use of corticosteroids may be justified in concert with the use of cytokine inhibitors such as tocilizumab (IL-6 inhibitor) or anakinra (IL-1 receptor antagonist). 11 Intravenous immune globulin (IVIG) may also play a role in modulating an immune system that is in a hyperinflammatory state. Overall, the prognosis and recovery from this critical stage of illness is poor, and rapid recognition and deployment of such therapy may have the greatest yield. The first open-label randomized controlled clinical trial of antiviral therapy was recently reported. 3 In this study, 199 patients were randomly allocated to the antiviral agents lopinavir–ritonavir or to standard of care and this regimen was not found to be particularly effective. One reason for this may have been that the patients were enrolled during the pulmonary stage with hypoxia (stage IIb) when the viral pathogenicity may have been only one lesser dominant aspect of the overall pathophysiology, and host inflammatory responses were the predominant pathophysiology We believe that this proposed 3-stage classification system for COVID-19 illness will serve to develop a uniform scaffold to build structured therapeutic experience as healthcare systems globally are besieged by this crisis, in patients with or without transplantation. Disclosure Dr. Siddiqi has nothing to declare. Dr. Mehra reports no direct conflicts pertinent to the development of this paper. Other general conflicts include consulting relationships with Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, NupulseCV, FineHeart, Leviticus and Triple Gene.
            Article 0 comments Cited 816 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults

              Catherine Lindgren, Assaf P. Oron, Daniel Li … (2017)
              Publisher's Note: There is an [Related article:] Inside Blood Commentary on this article in this issue. Defined-composition manufacturing platform of CD19 CAR T cells contributes to >90% intent-to-treat complete remission rate. Uniformity of durable persistence of CAR T cells and mitigation of antigen escape are key aspects for further optimization. Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 10 6 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease–negative (MRD − ) remission rate for this phase 1 study was 89%. The MRD − remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis. This trial was registered at www.clinicaltrials.gov as #NCT02028455.
              Article 0 comments Cited 458 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Pere Barba:
                ORCID: http://orcid.org/0000-0003-1038-5197
                pbarba@vhio.net
                Journal
                Journal ID (nlm-ta): Infection
                Journal ID (iso-abbrev): Infection
                Title: Infection
                Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )
                ISSN (Print): 0300-8126
                ISSN (Electronic): 1439-0973
                Publication date (Electronic): 26 September 2020
                Pages: 1-17
                Affiliations
                [1 ]GRID grid.411083.f, ISNI 0000 0001 0675 8654, Infectious Diseases Department, , Hospital Universitari Vall D’Hebron, ; Barcelona, Spain
                [2 ]GRID grid.7080.f, Department of Medicine, , Universitat Autònoma de Barcelona, ; Barcelona, Spain
                [3 ]GRID grid.411083.f, ISNI 0000 0001 0675 8654, Deparment of Hematology, Vall D’Hebron Institute of Oncology (VHIO), , Hospital Universitari Vall D’Hebron, ; Barcelona, Spain
                [4 ]GRID grid.7080.f, Department of Medicine, , Universitat Autònoma de Barcelona, ; Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
                [5 ]GRID grid.411109.c, ISNI 0000 0000 9542 1158, Department of Infectious Diseases, Microbiology and Preventive Medicine, , University Hospital Virgen del Rocío/CSIC/Institute of Biomedicine of Seville (IBIS), ; Seville, Spain
                [6 ]GRID grid.411160.3, ISNI 0000 0001 0663 8628, Clinical Immunology and Primary Immunodeficiencies Unit, , Hospital Sant Joan de Deu, ; Barcelona, Spain
                [7 ]GRID grid.411083.f, ISNI 0000 0001 0675 8654, Paediatric Oncology and Hematology Department, Hematopoietic Stem Cell Transplantation, , Hospital Universitari Vall D’Hebron, ; Barcelona, Spain
                [8 ]GRID grid.411160.3, ISNI 0000 0001 0663 8628, Infectious Diseases Unit, , Hospital Sant Joan de Deu, ; Barcelona, Spain
                [9 ]GRID grid.7080.f, Hematology Department, Hospital de La Santa Creu I Sant Pau, Sant Pau and Jose Carreras Leukemia Research Institutes, , Autonomous University of Barcelona, ; Barcelona, Spain
                [10 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Department of Infectious Diseases, Hospital Clínic, IDIBAPS (Institut D’Investigacions biomèdiques Agust Pi I Sunyer), , Universitat de Barcelona, ; Barcelona, Spain
                [11 ]GRID grid.411107.2, ISNI 0000 0004 1767 5442, Hematopoietic Stem Cell Transplantation and Cellular Therapy Unit, , Hospital Infantil Universitario “Niño Jesus”, ; Madrid, Spain
                [12 ]GRID grid.411308.f, Department of Hematology, , Hospital Clínico Universitario, Institute for Research INCLIVA, ; Valencia, Spain
                [13 ]GRID grid.410526.4, ISNI 0000 0001 0277 7938, Haematology and Haemotherapy Department, , Hospital General Universitario Gregorio Marañón, Gregorio Marañón Health Research Institute, ; Madrid, Spain
                [14 ]GRID grid.410526.4, ISNI 0000 0001 0277 7938, Clinical Microbiology and Infectious Diseases, , Hospital General Universitario Gregorio Marañón, Gregorio Marañón Health Research Institute, ; Madrid, Spain
                [15 ]GRID grid.7080.f, Epidemiology Department, Vall D’Hebron University Hospital, , Universitat Autònoma de Barcelona, ; Barcelona, Spain
                [16 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Department of Hematology, Hospital Clínic de Barcelona, Institut D’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), , University of Barcelona, ; Barcelona, Spain
                [17 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), , University of Barcelona, ; Barcelona, Spain
                [18 ]GRID grid.411308.f, Infectious Diseases Unit, , Hospital Clínico Universitario, Instituto de Investigación INCLIVA, ; Valencia, Spain
                [19 ]GRID grid.413448.e, ISNI 0000 0000 9314 1427, Hematology Division, , Hospital Universitario Y politécnico La Fe, Instituto de investigación sanitaria La Fe, Valencia, CIBERONC, Instituto Carlos III, ; Madrid, Spain
                [20 ]GRID grid.413396.a, ISNI 0000 0004 1768 8905, Infectious Disease Unit, Internal Medicine Department, , Hospital de La Santa Creu I Sant Pau, ; Barcelona, Spain
                [21 ]GRID grid.411109.c, ISNI 0000 0000 9542 1158, Department of Haematology, , University Hospital Virgen del Rocío/CSIC/Institute of Biomedicine of Seville (IBIS), ; Seville, Spain
                [22 ]GRID grid.84393.35, ISNI 0000 0001 0360 9602, Infectious Diseases Unit, , Área Clínica Médica, Hospital Universitario Y Politécnico La Fe, ; Valencia, Spain
                [23 ]GRID grid.411083.f, ISNI 0000 0001 0675 8654, Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital, , Universitari Vall D’Hebron, ; Barcelona, Spain
                [24 ]GRID grid.411258.b, Department of Haematology, , University Hospital of Salamanca, ; Salamanca, Spain
                Author information
                http://orcid.org/0000-0003-1038-5197
                Article
                Publisher ID: 1521
                DOI: 10.1007/s15010-020-01521-5
                PMC ID: 7518951
                PubMed ID: 32979154
                SO-VID: 34a29add-5b69-4fcd-947c-6ea08dcce634
                Copyright © © Springer-Verlag GmbH Germany, part of Springer Nature 2020
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 18 June 2020
                Date accepted : 29 August 2020
                Categories
                Subject: Review

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: chimeric antigen receptor,diffuse large b-cell lymphoma,b-cell acute lymphoblastic leukemia,bacterial infections,viral infections,fungal infections
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: chimeric antigen receptor, diffuse large b-cell lymphoma, b-cell acute lymphoblastic leukemia, bacterial infections, viral infections, fungal infections

                Comments

                Comment on this article

                scite_

                Similar content198

                See all similar

                Cited by38

                See all cited by

                Most referenced authors3,529

                See all reference authors