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The prognosis of allogeneic stem cell transplant recipients admitted to the intensive care unit (ICU) has improved over the last decades. However, data focusing on patients treated in the ICU during the peri-transplant period are scarce. We therefore conducted an analysis comprising 70 patients who had allogeneic stem cell transplantation at the University Hospital Cologne between 2014 and 2020 and were admitted to the ICU between the initiation of conditioning therapy and day 30 after transplantation. The median age was 59 years (range: 18 − 72 years). 50% of patients were female. Sepsis was the most common cause for ICU admission (49%). Mechanical ventilation (MV) was required in 56% of patients, 27% had renal replacement therapy (RRT), and 64% needed vasopressors. The ICU, hospital, 90-day, and 1-year survival rates were 48.6%, 38.6%, 35.7%, and 16.2%, respectively. MV and/or RRT during the ICU stay were associated with an impaired survival (p p n = 23), sepsis and other infectious complications represented the major causes of death (48%). Taken together, the present analysis indicates unfavorable outcomes for allogeneic stem cell transplant recipients admitted to the ICU during the peri-transplant period. The data may help to make informed decisions with patients and their families.

ZusammenfassungDie anhaltende Belastung der Mitarbeiter im Gesundheitsdienst während der COVID-19-Pandemie ist erheblich und stellt die Mitarbeiter vor große emotionale und psychologische Herausforderungen. In einer teaminternen Evaluation (Ärzt:innen und Pflegekräfte) wurden teamspezifische Belastungen, mögliche Entlastungsstrategien, positive und negative Erfahrungen sowie Wünsche für eine Verbesserung der Situation auf einer Intensivstation erhoben. Während beide Berufsgruppen gleich hohe emotionale Belastungsintensitäten wahrnahmen, werden bei der Pflege zusätzlich starke Belastungsintensitäten im organisatorischen und körperlichen Bereich wahrgenommen. Damit erweist sich die Berufsgruppe der Pflegenden als am stärksten durch die COVID-19-Pandemie belastet. Durch die hier herausgearbeiteten Erkenntnisse können für die Zukunft konkrete Handlungsanweisungen abgeleitet werden.

Due to acuteness, time constraints, and psychological pressure as well as changing team compositions, professional communication constitutes a key challenge in the treatment of critically ill patients.The aim of this narrative review is to present the current literature on clinical relevance and current developments of interdisciplinary and interprofessional communication in intensive care and emergency medicine.Effective communication is of great importance in intensive care and emergency medicine, both for ensuring high-quality patient care and work satisfaction as well as mental health of the medical practitioners. Most conflicts occur between the medical and nursing staff, with communicative conflicts predominantly being related to discussions about the patient's prognosis and end-of-life decision-making. Structural measures such as regular team meetings and trainings seem suitable to specifically improve communication. However, the topic is commonly inadequately represented in everyday clinical practice as well as in research.Even though the importance of interprofessional and interdisciplinary communication for high-quality patient care and workload reduction is increasingly being recognized, its routine application in everyday clinical practice is still scarce, particularly in intensive care and emergency medicine. Due to the specific structure and patient population of these fields of patient care, they can benefit more than other specialties from targeted measures to improve communication.HINTERGRUND: Bei der Behandlung kritisch kranker Patient*innen stellt eine professionelle Kommunikation aufgrund der Akuität, des hohen zeitlichen und psychischen Drucks sowie wechselnder personeller Konstellationen verschiedener Berufsgruppen eine besondere Herausforderung dar.Das Ziel ist eine Darstellung der Bedeutung und aktueller Entwicklungen der interdisziplinären und interprofessionellen Kommunikation in der Intensiv- und Notfallmedizin im Rahmen einer narrativen Übersichtsarbeit anhand der aktuellen Literatur.Eine effektive Kommunikation spielt in der Intensiv- und Notfallmedizin eine zentrale Rolle. Dies gilt sowohl für die Qualität der Patient*innenversorgung als auch für die Arbeitszufriedenheit und psychische Gesundheit des Behandlungsteams. Dabei treten die häufigsten Konflikte zwischen ärztlichem und pflegerischem Personal auf und betreffen insbesondere Diskussionen bezüglich Prognose und Entscheidungen am Lebensende. Einfache strukturelle Maßnahmen, wie regelmäßige Teambesprechungen und Schulung kommunikativer Kompetenzen, stellen geeignete Maßnahmen dar, um die Kommunikation gezielt zu verbessern. Aktuell sind diese Maßnahmen in klinischem Alltag und Forschung jedoch zumeist deutlich unterrepräsentiert.Auch wenn die Bedeutung interprofessioneller und interdisziplinärer Kommunikation für die Versorgungsqualität und die Arbeitsbelastung zunehmend erkannt wird, wird diesem Thema im klinischen Alltag zu wenig Aufmerksamkeit geschenkt. Dies gilt insbesondere in der Intensiv- und Notfallmedizin, die fachbedingt immens von gezielten Maßnahmen zur Verbesserung der Kommunikation profitieren kann.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) can be associated with adverse events necessitating treatment on the intensive care unit (ICU). Data focusing on patients admitted to the ICU during hospitalization for high-dose chemotherapy and ASCT are scarce. We thus conducted a single-center retrospective analysis comprising 79 individuals who had high-dose chemotherapy and ASCT between 2014 and 2020 and were admitted to the ICU between the initiation of conditioning therapy and day 30 after ASCT. The median age was 57 years (range: 20–82 years); 38% of patients were female. B-cell non-Hodgkin lymphoma (34%) and plasma cell disorders (28%) were the most common indications for high-dose chemotherapy and ASCT. Sepsis represented the major cause for ICU admission (68%). Twenty-nine percent of patients required mechanical ventilation (MV), 5% had renal replacement therapy, and 44% needed vasopressors. The ICU, hospital, 90-day, and 1-year survival rates were 77.2%, 77.2%, 72.2%, and 60.3%, respectively. Stable disease or disease progression prior to the initiation of high-dose chemotherapy (p = 0.0028) and MV (p

Die Transfusion von Chimaren-Antigenrezeptor(CAR)-T-Zellen hat sich als neue Therapieform in der Onkologie etabliert, geht jedoch regelhaft mit immunvermittelten Nebenwirkungen einher, die auch schwer verlaufen konnen sowie eine spezifische und intensivmedizinische Behandlung erfordern. Literaturrecherche zu CAR-T-Zell-Therapie, Toxizitaten und Nebenwirkungsmanagement. Das „cytokine release syndrome“ (CRS) und das „immune effector cell-associated neurotoxicity syndrome“ (ICANS) treten regelhaft kurz nach einer Therapie mit CAR-T-Zellen auf. Das CRS kann von einer milden grippeahnlichen Symptomatik bis zum Multiorganversagen fuhren. Beim ICANS kann es neben milden Symptomen wie Verwirrtheit und Aphasie auch zu Krampfanfallen und Hirnodem kommen. Das Management von CRS und ICANS orientiert sich am Schweregrad nach dem Grading der American Society for Transplantation and Cellular Therapy (ASTCT). Beim CRS werden Tocilizumab und Kortikosteroide empfohlen; beim ICANS werden Kortikosteroide eingesetzt. Im weiteren Verlauf sind eine persistierende Hypogammaglobulinamie und Zytopenien auch Monate nach der Therapie haufig; diese begunstigen Infektionen auch Monate nach CAR-T-Zell-Therapie. Nach CAR-T-Zell-Therapie kommt es regelhaft zu potenziell schweren Komplikationen. Eine interdisziplinare Zusammenarbeit zwischen Intensivmediziner*innen, Hamatolog*innen, Neurolog*innen und Arzt*innen anderer Fachabteilungen ist fur die optimale Versorgung von CAR-T-Zell-Patient*innen von entscheidender Bedeutung.

Summary Background Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care. Methods This international, multicentre, observational cohort study was done in 21 intensive care units in France, Spain, the USA, the UK, Russia, Canada, Germany, and Austria. Eligible patients were aged 18 years or older; had received CAR T-cell therapy in the past 30 days; and had been admitted to intensive care for any reason. Investigators retrospectively included patients admitted between Feb 1, 2018, and Feb 1, 2019, and prospectively included patients admitted between March 1, 2019, and Feb 1, 2020. Demographic, clinical, laboratory, treatment, and outcome data were extracted from medical records. The primary endpoint was 90-day mortality. Factors associated with mortality were identified using a Cox proportional hazard model. Findings 942 patients received CAR T-cell therapy, of whom 258 (27%) required admission to intensive care and 241 (26%) were included in the analysis. Admission to intensive care was needed within median 4·5 days (IQR 2·0–7·0) of CAR T-cell infusion. 90-day mortality was 22·4% (95% CI 17·1–27·7; 54 deaths). At initial evaluation on admission, isolated cytokine release syndrome was identified in 101 patients (42%), cytokine release syndrome and ICANS in 93 (39%), and isolated ICANS in seven (3%) patients. Grade 3–4 cytokine release syndrome within 1 day of admission to intensive care was found in 50 (25%) of 200 patients and grade 3–4 ICANS in 38 (35%) of 108 patients. Bacterial infection developed in 30 (12%) patients. Life-saving treatments were used in 75 (31%) patients within 24 h of admission to intensive care, primarily vasoactive drugs in 65 (27%) patients. Factors independently associated with 90-day mortality by multivariable analysis were frailty (hazard ratio 2·51 [95% CI 1·37–4·57]), bacterial infection (2·12 [1·11–4·08]), and lifesaving therapy within 24 h of admission (1·80 [1·05–3·10]). Interpretation Critical care management is an integral part of CAR T-cell therapy and should be standardised. Studies to improve infection prevention and treatment in these high-risk patients are warranted. Funding Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique.

Was ist neu? CRS und ICANS als Nebenwirkung von CAR-T-Zellen Das Cytokine-Release-Syndrome (CRS) ist die häufigste Nebenwirkung einer CAR-T-Zell-Therapie und kann von leichtem Fieber bis zu einem Multiorganversagen führen. Pathophysiologisch kommt es beim CRS zu einem Zytokinsturm und trotz einer Therapie mit Tocilizumab sind refraktäre und tödliche Verläufe beschrieben. Die Symptome des Immune-Effector-Cell-associated-Neurotoxicity-Syndrome (ICANS) variieren von leichter Desorientiertheit bis zum lebensbedrohlichen Hirnödem. Die Pathophysiologie und Therapie des ICANS sind noch nicht ausreichend erforscht. Die Differenzialdiagnosen von CRS und ICANS sind komplex und umfassen neben Infektionen und Sepsis unter anderem auch eine Toxizität der vorhergehenden Therapie, ein Tumorlysesyndrom und nicht zuletzt einen Progress der Grunderkrankung. Ein klinischer oder laborchemischer Parameter zum sicheren Beweis oder Ausschluss eines CRS oder ICANS gibt es zum heutigen Zeitpunkt nicht. Intensivmedizinische Relevanz und potenzielle Entwicklungen der CAR-T-Zell-Therapie Erste Auswertungen von Real-world-Daten deuten auf eine höhere Rate an schweren Nebenwirkungen im Rahmen der CAR-T-Zell-Therapie als in den Zulassungsstudien hin. Für die Indikation r/r-DLBCL könnten schätzungsweise bis zu maximal 300 Patienten pro Jahr in Deutschland eine intensivmedizinische Betreuung im Rahmen der CAR-T-Zell-Therapie benötigen. Studien mit wesentlich häufigeren soliden Tumoren könnten die Patientenzahl drastisch erhöhen. Therapieziel bei CAR-T-Zell-Patienten und Entscheidungen bei Therapiezieländerung Aufgrund des neuen Therapiekonzepts kann ein Konflikt zwischen bislang palliativem Patientenkollektiv und nun möglicherweise langfristigen Remissionen entstehen. Eine frühzeitige Aufklärung über potenziell lebensbedrohliche Nebenwirkungen im Rahmen der Therapie und eine interdisziplinäre Besprechung der Therapieziele mit den Patienten ist entscheidend.

Metastatic pulmonary calcification is an underdiagnosed metabolic lung disease characterized by diffuse calcium deposition in the lungs, often associated with secondary hyperparathyroidism due to chronic renal failure. A 31-year-old man with chronic renal failure initially presented with diffuse pain symptoms, deterioration of general condition, and respiratory insufficiency. Noncontrast-enhanced computed tomography of the chest was performed using a spectral-detector-based dual-energy CT. It showed multiple, centrilobular, ground-glass opacities, and nodules, ultimately leading to the diagnosis. Calcium suppression proved to be highly useful to classify the pulmonary alterations.

Introduction: Over the last decade targeted therapies have transformed the treatment landscape for hematologic malignancies with >70 new or extended approvals by the FDA since 2010. Since many of these drugs are registered for multiple entities and >1/3 were approved in the last two years, treatment options in hematology are rapidly expanding. Despite the justified excitement around the often previously unseen emerging therapeutic potential, distinct side-effect profiles require vigilance and adequate management by patients and caregivers.Areas covered: This review provides a summary of the unique toxicity profiles of therapies for hematologic malignancies during the last decade with a focus on clinical implications and applicability. Due to the already wide implementation in common practice or an immense potential thereof selected treatments such as immune checkpoint inhibitors, various monoclonal antibodies, tyrosine kinase inhibitors and CAR T-cell therapies are discussed in detail. Challenges and potential strategies to assess and manage real-world toxicity after drug approval are addressed.Expert opinion: The rapidly expanding therapeutic landscape of hematologic malignancies comes with a broad spectrum of side effects which are distinct from conventional hematotoxicity and require alertness.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts hemostasis and microvasculature. In the light of the dilemma between thromboembolic and hemorrhagic complications, in the present paper, we systematically investigate the prevalence, mortality, radiological subtypes, and clinical characteristics of intracranial hemorrhage (ICH) in coronavirus disease (COVID-19) patients. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. We performed a pooled analysis, including a prospectively collected cohort of critically ill COVID-19 patients with ICH, as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive Care of COVID-19). Results: Our literature review revealed a total of 217 citations. After the selection process, 79 studies and a total of 477 patients were included. The median age was 58.8 years. A total of 23.3% of patients experienced the critical stage of COVID-19, 62.7% of patients were on anticoagulation and 27.5% of the patients received ECMO. The prevalence of ICH was at 0.85% and the mortality at 52.18%, respectively. Conclusion: ICH in COVID-19 patients is rare, but it has a very poor prognosis. Different subtypes of ICH seen in COVID-19, support the assumption of heterogeneous and multifaceted pathomechanisms contributing to ICH in COVID-19. Further clinical and pathophysiological investigations are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future.

The ongoing strain on personnel in the healthcare system during the COVID-19 pandemic is considerable and poses major emotional and psychological challenges for the personnel. In a team evaluation (physicians and nurses), team-specific stress, possible relief strategies, positive and negative experiences, and wishes for improvement of the situation in an intensive care unit were collected. While both occupational groups perceived equally high emotional stress intensities, nursing additionally perceived high stress intensities in the organizational and physical areas. Thus, the occupational group of nurses proves to be the most stressed by the COVID-19 pandemic. The findings presented here can be used to derive instructions for future actions.Die anhaltende Belastung der Mitarbeiter im Gesundheitsdienst während der COVID-19-Pandemie ist erheblich und stellt die Mitarbeiter vor große emotionale und psychologische Herausforderungen. In einer teaminternen Evaluation (Ärzt:innen und Pflegekräfte) wurden teamspezifische Belastungen, mögliche Entlastungsstrategien, positive und negative Erfahrungen sowie Wünsche für eine Verbesserung der Situation auf einer Intensivstation erhoben. Während beide Berufsgruppen gleich hohe emotionale Belastungsintensitäten wahrnahmen, werden bei der Pflege zusätzlich starke Belastungsintensitäten im organisatorischen und körperlichen Bereich wahrgenommen. Damit erweist sich die Berufsgruppe der Pflegenden als am stärksten durch die COVID-19-Pandemie belastet. Durch die hier herausgearbeiteten Erkenntnisse können für die Zukunft konkrete Handlungsanweisungen abgeleitet werden.

To map the existing approaches to communication with family members of the critically ill in the intensive care unit and the corresponding implementation requirements and benefits.We conducted a scoping review in February 2022 by searching PubMed, CINAHL, APA PsycINFO, and Cochrane Library for articles published between 2000 and 2022. We included records of all designs that met our inclusion criteria and applied frequency counts and qualitative coding.The search yielded 3749 records, 63 met inclusion criteria. The included records were of an interventional (43 %) or observational (14 %) study design or review articles (43 %), and provided information in three categories: communication platforms, strategies, and tools. For implementation in the intensive care unit, the approaches required investing time and resources. Their reported benefits were an increased quality of communication and satisfaction among all parties involved, improved psychological outcome among family members, and reduced intensive care unit length of stay and costs.The current approaches to communication with patients' family members offer insights for the development and implementation of communication pathways in the intensive care unit of which the benefits seem to outweigh the efforts. Structured interprofessional frameworks with standardised tools based on empathic communication strategies are encouraged.

The combination of coronavirus disease 2019 (COVID-19) pneumonia and pulmonary–renal syndrome due to ANCA-associated vasculitis (AAV) poses diagnostic uncertainty and a therapeutic dilemma. According to current limited knowledge of COVID-19, the application of commonly used drugs in AAV, cyclophosphamide (CYC) and rituximab (RTX), must be weighed carefully in active COVID-19 infection. We report a case of a 52-year-old male patient with concurrent severe COVID-19 pneumonia and acute relapse of pulmonary–renal syndrome due to AAV after recent RTX maintenance dose. The patient presented with severe hypoxaemia, complete B-cell depletion and severe acute respiratory syndrome coronavirus 2 viraemia. He was successfully treated with therapeutic plasma exchange employing COVID-19 convalescent plasma.

The alpha variant of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is associated with higher transmissibility and possibly higher mortality compared with wild-type SARS-CoV-2. However, few data are available on the clinical course of infections with the alpha variant compared with wild-type SARS-CoV-2 in critically ill patients in intensive care units (ICUs). Therefore, we retrospectively analyzed patients admitted to our ICU due to SARS-CoV-2 Alpha variant infection and compared characteristics and course to patients with SARS-CoV-2 wild-type infection. The median age of patients with Alpha variant infections was 57 years compared to 62 years in the wild-type group. ICU survival was 41/80 (51%) in the Alpha variant group and 35/80 (44%) in the wild-type group (p = 0.429). Results of a matched-pair analysis based on age and sex illustrated that 45/58 patients (77.6%) in the Alpha variant group and 38/58 (65.5%) patients in the wild-type group required mechanical ventilation (p = 0.217). ICU survival was documented for 28/58 patients (48.3%) in the Alpha variant group and 27/58 patients (46.6%) in the wild-type group (p = 1). Thus, ICU mortality among patients with SARS-CoV-2 infections remains high. Although the Alpha variant group included younger patients requiring mechanical ventilation, no significant differences between patients with the SARS-CoV-2 Alpha variant and the SARS-CoV-2 wild-type, respectively, were detected with respect to clinical course and ICU mortality. For future VOCs, we believe it would be important to obtain valid and rapid data on the clinical course of critically ill patients who test positive for COVID-19 in order to perform appropriate epidemiological planning of intensive care capacity.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts on hemostasis and microvasculature. Correspondingly, antithrombotic therapy is frequently used for prophylaxis or treatment of thromboembolic complications as well as in the context of extracorporeal membrane oxygenation (ECMO). However, reports of intracranial hemorrhage (ICH) associated with Coronavirus disease 2019 (COVID-19) have also emerged. In the light of the dilemma between thromboembolic and hemorrhagic complications, we sought to systematically investigate incidence, mortality, radiological subtypes and clinical characteristics of ICH in COVID-19 patients.Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. Furthermore, we performed a pooled analysis including a prospectively collected cohort of critically ill COVID-19 patients with ICH as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive care of COVID-19).Results: Our literature review revealed a total of 217 citations. After selection process, 79 studies and a total of 477 patients were included. Median age was 58.8 years (95% CI 54.8 years-62.9 years; I2 = 85,6%). 23.3% patients experienced critical stage of COVID-19 (95% CI 8.9% − 61.2%, I2 = 53.8%). 62.7% patients were on anticoagulation (95% CI 38.2% − 103.0%, I2 = 82,6%), and 27.5% patients received ECMO (95% CI 5.8% − 130.2%, I2 = 92.7%). Microbleeds (51.1%, 95% CI 31.1% − 84.2%, I2 = 85.1%), subarachnoid hemorrhage (SAH) (26.6%, 95% CI 16.8% − 42.0%, I2 = 61.2%) and intraparenchymal hemorrhage (IPH) (33.7%, 95% CI 23.3% − 48.8%, I2 = 63.7%) were most frequently documented as ICH subtypes. Incidence was at 0.85% (95% CI 0.36%-1.99%; I2 = 97.5%) and mortality at 52.18% (95% CI 40.40%-67.39%; I2 = 51.7%), respectively.Conclusion: ICH in COVID-19 patients is rare, but has a very poor prognosis. Different subtypes of ICH seen in COVID-19 support the assumption of heterogenous and multifactorial pathomechanisms contributing to ICH in COVID-19. Further data and pathophysiological insights are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future.

CAR-T cells, genetically modified tumor-targeted t-cells, revolutionized the treatment of refractory B-cell malignancies. CAR-T cell treatment however, is invariably associated with severe immune-mediated toxicities, namely Cytokine Release Syndrome (CRS) and neurological toxicity (CRES/ICANS). Although knowledge on the pathomechanism of these toxicities is still very limited, recent findings including mouse models might allow prediction, earlier recognition and targeted treatment of patients suffering from these potentially life-threatening side effects. This article summarizes current knowledge and recent findings on the management of severe CAR-T associated toxicities and gaps of knowledge stressing the importance of an interdisciplinary approach including hematology-oncology and Intensive Care Medicine.

The transfusion of chimeric antigen receptor (CAR) T‑cells has become established as a new treatment option in oncology; however, this is regularly associated with immune-mediated side effects, which can also run a severe course and necessitate a specific treatment and intensive medical treatment.A literature review was carried out on CAR T-cell therapy, toxicities and the management of side effects.The cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS) regularly occur shortly after CAR T-cell treatment. The symptoms of CRS can range from mild flu-like symptoms to multiorgan failure. In addition to mild symptoms, such as disorientation and aphasia, ICANS can also lead to convulsive seizures and brain edema. The management of CRS and ICANS is based on the severity according to the grading of the American Society for Transplantation and Cellular Therapy (ASTCT). Tocilizumab and corticosteroids are recommended for CRS and corticosteroids are used for ICANS. In the further course persisting hypogammaglobulinemia and cytopenia are frequent even months after the initial treatment and promote infections even months after CAR T‑cell therapy.Potentially severe complications regularly occur after CAR T-cell therapy. An interdisciplinary cooperation between intensive care physicians, hematologists, neurologists and specialists in other disciplines is of decisive importance for the optimal care of patients after CAR T‑cell therapy.HINTERGRUND: Die Transfusion von Chimären-Antigenrezeptor(CAR)-T-Zellen hat sich als neue Therapieform in der Onkologie etabliert, geht jedoch regelhaft mit immunvermittelten Nebenwirkungen einher, die auch schwer verlaufen können sowie eine spezifische und intensivmedizinische Behandlung erfordern.Literaturrecherche zu CAR-T-Zell-Therapie, Toxizitäten und Nebenwirkungsmanagement.Das „cytokine release syndrome“ (CRS) und das „immune effector cell-associated neurotoxicity syndrome“ (ICANS) treten regelhaft kurz nach einer Therapie mit CAR-T-Zellen auf. Das CRS kann von einer milden grippeähnlichen Symptomatik bis zum Multiorganversagen führen. Beim ICANS kann es neben milden Symptomen wie Verwirrtheit und Aphasie auch zu Krampfanfällen und Hirnödem kommen. Das Management von CRS und ICANS orientiert sich am Schweregrad nach dem Grading der American Society for Transplantation and Cellular Therapy (ASTCT). Beim CRS werden Tocilizumab und Kortikosteroide empfohlen; beim ICANS werden Kortikosteroide eingesetzt. Im weiteren Verlauf sind eine persistierende Hypogammaglobulinämie und Zytopenien auch Monate nach der Therapie häufig; diese begünstigen Infektionen auch Monate nach CAR-T-Zell-Therapie.Nach CAR-T-Zell-Therapie kommt es regelhaft zu potenziell schweren Komplikationen. Eine interdisziplinäre Zusammenarbeit zwischen Intensivmediziner*innen, Hämatolog*innen, Neurolog*innen und Ärzt*innen anderer Fachabteilungen ist für die optimale Versorgung von CAR-T-Zell-Patient*innen von entscheidender Bedeutung.

Summary Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding Sanofi and Regeneron Pharmaceuticals.

Background: Coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome patients are at risk for fungal infections, especially aspergillosis and mucormycosis. COVID-19-associated pulmonary aspergillosis (CAPA) is differentiated in a pulmonary form and Aspergillus tracheobronchitis (ATB). During the first wave of the pandemic, bronchoscopy for diagnosing Aspergillus superinfections was rarely performed in COVID-19 patients, so that detailed on data on ATB in CAPA patients is scarce. We analyzed prevalence and mortality of tracheobronchitis in patients with CAPA. Methods: We conducted a retrospective, single-centre study at the 14-bed intensive care unit (ICU) of the Department I of Internal Medicine of the University Hospital of Cologne, Germany from March 2020 to February 2021. CAPA patients were identified by twice weekly analysis of tracheal aspirates for Aspergillus growth, Aspergillus DNA (PCR) and galactomannan combined with serum galactomannan testing. In case of positive results, bronchoscopy with the examination of trachea and lower airways and bronchoalveolar lavage followed. Findings: A total of 69 COVID-19 patients were admitted to the ICU, with 17 patients developing probable CAPA. All CAPA patients received bronchoscopy resulting in a clinical diagnosis of tracheobronchitis in 8 patients with signs of tracheal lesions, pseudomembranes or vulnerable bloody trachea. Seven bronchoalveolar lavages revealed culture and eight PCR positivity for Aspergillus fumigatus. In 7 of 8 tracheobronchitis patients, bronchoalveolar lavage samples tested positive for galactomannan antigen optical density index of >0.5. The overall mortality of CAPA patients was 52.9% and the overall mortality of ATB patients was 75%. Interpretation: Our data indicate a substantial prevalence of tracheobronchitis in this single-center cohort of CAPA patients. To facilitate early diagnosis bronchoscopic tracheal examination is crucial as computed tomography lacks diagnostic accuracy to enable timely initiation of therapy. Funding Information: This work was in part supported by the German Registry of COVID-19 Autopsies (www.DeRegCOVID.ukaachen.de), funded by the Federal Ministry of Health (ZMVI1-2520COR201), and the project DEFEAT PANDEMICs, funded by the Federal Ministry of Education and Research (01KX2021). Declaration of Interests: PK reports grants or contracts from German Federal Ministry of Research and Education and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie fur Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, medupdate GmbH, MedMedia, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicacion Cientifica SC and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. SvS none. JGB reports scientific grants and travel expenses from Kite/Gilead outside the submitted work. FF has a clinician scientist position supported by the deans office, medical faculty, University of Cologne. JSG none. FP none. BB reports honoraria, travel expenses and advisory role from/for Astellas, Celgene, Johnson & Johnson, Kite/Gilead, MSD, Novartis, Pfizer, Takeda and financing of scientific research by Astellas, Celgene, Kite/Gilead, MSD and Takeda outside the submitted work. DAE received honoraria from Sanofi and TAKEDA outside the submitted work. ASV reports travel grants from Gilead Sciences outside the submitted work. OK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead and Pfizer and receipt of equipment, materials, drugs, medical writing, gifts or other services by Pfizer, MSD, Basilea, Gilead, Virotech and Wako Fujifilm outside the submitted work. PB none. MK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead, MSD and Pfizer outside the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Al 344 Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Pfizer; Payment for expert testimony from Cidara; Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, Wiley outside the submitted work. Ethics Approval Statement: Patients with CAPA were included in the FungiScope® global registry for emerging invasive fungal infections (https://www.clinicaltrials.gov; National Clinical Trials identifier NCT01731353), which was approved by the local ethics committee of the University of Cologne, Cologne, Germany (identifier 05-102).

Introduction Non-bacterial thrombotic endocarditis (NBTE) is characterised by non-infectious vegetations on the cardiac valves and is typically seen in patients with malignancies or systemic lupus erythematosus. Risk of thromboembolic events is high and treatment of choice consists of anticoagulation, if feasible, as well as treatment of the underlying disease. Severe valvular dysfunction is rarely seen and in these cases, surgical valve replacement is usually performed. Case presentation A 28-year old female patient presented with left-sided hemiparesis persisting for several hours. Angio-CT scan of the brain revealed a branch occlusion of the middle cerebral artery with a correlating infarct core and without an area of penumbra. Blood tests showed decreased thrombocyte levels (45 x109/l). Given the thrombocytopenia and the time between the onset of symptoms and presentation, no thrombolysis was administered. A subsequently performed transoesophageal echocardiography for diagnostic work-up of cardioembolic sources of stroke revealed a right ventricular thrombus and vegetations on the aortic valve causing severe aortic regurgitation with a holodiastolic flow reversal in the descending aorta (Fig. 1 (a) and (b) showing a large central coaptation defect). There were no of signs of infection or inflammation and blood cultures remained negative, thus infectious endocarditis was unlikely. A bone marrow biopsy led to the diagnosis of acute promyeolocytic leukemia (PML). Despite the inherent high risk of bleeding due to PML, anticoagulation with unfractionated heparin was initiated and treatment with prednisolone, all-trans retinoic acid and arsenic trioxide was started. After three weeks of therapy aortic valve vegetation size decreased considerably leading to dramatic reduction of aortic regurgitation (Fig. 1 (c) and (d)). No further embolic event or bleeding occurred. Conclusion This case is remarkable in many aspects. First, PML typically causes bleeding complications whereas NBTE is characterised by a high risk of thromboembolic events. Thus, the decision to start or not to start anticoagulation is challenging. Second, NBTE, unlike infectious endocarditis, rarely causes severe valvular dysfunction and reported treatment in most cases consisted of surgical valve replacement or repair. However, in this case, conservative treatment alone led to almost complete resolution of valvular vegetations and of aortic regurgitation. We conclude that conservative treatment of severe valvular disease in the setting of NBTE should be strongly considered, especially given the small number of cases reported worldwide. Abstract P630 Figure. Fig.1

CAR T-cell treatment has brought a significant benefit for patients with relapsed and refractory lymphoma and even long lasting remissions seem to be possible. Despite the good results CAR T-cell treatment is associated with severe and potentially life-threatening adverse effects. Patients regularly develop Cytokine Release Syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) after the transfusion of CAR T-cells. In addition to these immunological reactions patients can develop severe and life-threatening infections and other related adverse effects. Due to the increasing number of patients receiving CAR T-cells and the upcoming clinical trials more and more patients will potentially require intensive care treatment for the adverse effects after CAR T-cell treatment. The management of these patients requires an extensive diagnostic workup and complex treatment. An interdisciplinary team of hematologist, intensivist and others like neurologist and palliative medicine consultants is crucial for the best treatment of these patients. Together with the increasing number of patients this can lead to logistical issues for the intensive care departments of centers offering CAR T-cell therapies.Das Cytokine-Release-Syndrome (CRS) ist die häufigste Nebenwirkung einer CAR-T-Zell-Therapie und kann von leichtem Fieber bis zu einem Multiorganversagen führen. Pathophysiologisch kommt es beim CRS zu einem Zytokinsturm und trotz einer Therapie mit Tocilizumab sind refraktäre und tödliche Verläufe beschrieben. Die Symptome des Immune-Effector-Cell-associated-Neurotoxicity-Syndrome (ICANS) variieren von leichter Desorientiertheit bis zum lebensbedrohlichen Hirnödem. Die Pathophysiologie und Therapie des ICANS sind noch nicht ausreichend erforscht. Die Differenzialdiagnosen von CRS und ICANS sind komplex und umfassen neben Infektionen und Sepsis unter anderem auch eine Toxizität der vorhergehenden Therapie, ein Tumorlysesyndrom und nicht zuletzt einen Progress der Grunderkrankung. Ein klinischer oder laborchemischer Parameter zum sicheren Beweis oder Ausschluss eines CRS oder ICANS gibt es zum heutigen Zeitpunkt nicht. INTENSIVMEDIZINISCHE RELEVANZ UND POTENZIELLE ENTWICKLUNGEN DER CAR-T-ZELL-THERAPIE: Erste Auswertungen von Real-world-Daten deuten auf eine höhere Rate an schweren Nebenwirkungen im Rahmen der CAR-T-Zell-Therapie als in den Zulassungsstudien hin. Für die Indikation r/r-DLBCL könnten schätzungsweise bis zu maximal 300 Patienten pro Jahr in Deutschland eine intensivmedizinische Betreuung im Rahmen der CAR-T-Zell-Therapie benötigen. Studien mit wesentlich häufigeren soliden Tumoren könnten die Patientenzahl drastisch erhöhen. THERAPIEZIEL BEI CAR-T-ZELL-PATIENTEN UND ENTSCHEIDUNGEN BEI THERAPIEZIELäNDERUNG: Aufgrund des neuen Therapiekonzepts kann ein Konflikt zwischen bislang palliativem Patientenkollektiv und nun möglicherweise langfristigen Remissionen entstehen. Eine frühzeitige Aufklärung über potenziell lebensbedrohliche Nebenwirkungen im Rahmen der Therapie und eine interdisziplinäre Besprechung der Therapieziele mit den Patienten ist entscheidend.

CAR-T cells, genetically modified tumor-targeted t-cells, revolutionized the treatment of refractory B-cell malignancies. CAR-T cell treatment however, is invariably associated with severe immune-mediated toxicities, namely Cytokine Release Syndrome (CRS) and neurological toxicity (CRES/ICANS). Although knowledge on the pathomechanism of these toxicities is still very limited, recent findings including mouse models might allow prediction, earlier recognition and targeted treatment of patients suffering from these potentially life-threatening side effects. This article summarizes current knowledge and recent findings on the management of severe CAR-T associated toxicities and gaps of knowledge stressing the importance of an interdisciplinary approach including hematology-oncology and Intensive Care Medicine.

Background With Sepsis-3, the increase in sequential organ failure assessment (SOFA) as a clinical score for the identification of patients with sepsis and quickSOFA (qSOFA) for the identification of patients at risk of sepsis outside the intensive care unit (ICU) were introduced in 2016. However, their validity has been questioned, and their applicability in different settings and subgroups, such as hematological cancer patients, remains unclear. We therefore assessed the validity of SOFA, qSOFA, and the systemic inflammatory response syndrome (SIRS) criteria regarding the diagnosis of sepsis and the prediction of in-hospital mortality in a multicenter cohort of hematological cancer patients treated on ICU and non-ICU settings. Methods We retrospectively calculated SIRS, SOFA, and qSOFA scores in our cohort and applied the definition of sepsis as “life-threatening organ dysfunction caused by dysregulated host response to infection” as reference. Discriminatory capacity was assessed using the area under the receiver operating characteristic curve (AUROC). Results Among 450 patients with hematological cancer (median age 58 years, 274 males [61%]), 180 (40%) had sepsis of which 101 (56%) were treated on ICU. For the diagnosis of sepsis, sensitivity was 86%, 64%, and 42% for SIRS, SOFA, and qSOFA, respectively. However, the AUROCs of SOFA and qSOFA indicated better discrimination for sepsis than SIRS (SOFA, 0.69 [95% CI, 0.64–0.73] p

The success of chimeric antigen receptor (CAR)-T cell therapy with impressive response rates in hematologic malignancies but also promising data in solid tumors came along with the cognition of unexpected, potentially life-threatening immune-mediated toxicities, namely the cytokine release syndrome (CRS) and neurotoxicity recently referred to as “immune effector cell-associated neurotoxicity syndrome” (ICANS). These toxicities require urgent diagnostic and therapeutic interventions and targeted modulation of key cytokine pathways represents the mainstay of CRS treatment. However, as the underlying mechanisms of ICANS are not well understood, treatment options remain limited and further investigation is warranted. Importantly, after the recent market approval of 2 CAR-T cell constructs, the application of CAR-T cells will expand to nonacademic centers with limited experience in the management of CAR-T cell-associated toxicities. Here, we review the current evidence of CRS and ICANS pathophysiology, diagnostics, and treatment.