Outcomes in Critically Ill Allogeneic Hematopoietic Stem-Cell Transplantation Recipients.

Rationale: Allogeneic hematopoietic stem-cell transplantation (Allo-HSCT) recipients are still believed to be poor candidates for ICU management. Methods: We investigated outcomes and determinants of mortality in a large multicenter retrospective cohort of Allo-HSCT patients admitted between January 1, 2015, and December 31, 2020, to 14 French ICUs. The primary endpoint was 90-day mortality. Measurements and Main Results: In total, 1,164 patients were admitted throughout the study period. At the time of ICU admission, 765 (66%) patients presented with multiple organ dysfunction, including acute respiratory failure in 40% (n = 461). The median sepsis-related organ failure assessment score was 6 (interquartile range, 4-8). Invasive mechanical ventilation, renal replacement therapy, and vasopressors were required in 438 (38%), 221 (19%), and 468 (41%) patients, respectively. ICU mortality was 26% (302 deaths). Ninety-day, 1-year, and 3-year mortality rates were 48%, 63%, and 70%, respectively. By multivariable analysis, age > 56 years (odds ratio [OR], 2.0 [95% confidence interval (CI), 1.53-2.60]; P < 0.001), time from Allo-HSCT to ICU admission between 30 and 90 days (OR, 1.68 [95% CI, 1.17-2.40]; P = 0.005), corticosteroid-refractory acute graft-versus-host disease (OR, 1.63 [95% CI, 1.38-1.93]; P < 0.001), need for vasopressors (OR, 1.9 [95% CI, 1.42-2.55]; P < 0.001), and mechanical ventilation (OR, 3.1 [95% CI, 2.29-4.18]; P < 0.001) were independently associated with 90-day mortality. In patients requiring mechanical ventilation, mortality rates ranged from 39% (no other risk factors for mortality) to 100% (four associated risk factors for mortality). Conclusions: Most critically ill Allo-HSCT recipients survive their ICU stays, including those requiring mechanical ventilation, with an overall 90-day survival rate reaching 51.8%. A careful assessment of goals of care is required in patients with two or more risk factors for mortality.

Multicenter Retrospective Study of Invasive Fusariosis in Intensive Care Units, France.

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002----2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

Severe infections requiring intensive care unit admission in patients receiving ibrutinib for hematological malignancies: a groupe de recherche respiratoire en réanimation onco-hématologique (GRRR-OH) study.

BACKGROUND: In the last decade, Ibrutinib has become the standard of care in the treatment of several lymphoproliferative diseases such as chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphoma. Beyond Bruton tyrosine kinase inhibition, Ibrutinib shows broad immunomodulatory effects that may promote the occurrence of infectious complications, including opportunistic infections. The infectious burden has been shown to vary by disease status, neutropenia, and prior therapy but data focusing on severe infections requiring intensive care unit (ICU) admission remain scarce. We sought to investigate features and outcomes of severe infections in a multicenter cohort of 69 patients receiving ibrutinib admitted to 10 French intensive care units (ICU) from 1 January 2015 to 31 December 2020. RESULTS: Median time from ibrutinib initiation was 6.6 [3-18] months. Invasive fungal infections (IFI) accounted for 19% (n = 13/69) of severe infections, including 9 (69%; n = 9/13) invasive aspergillosis, 3 (23%; n = 3/13) Pneumocystis pneumonia, and 1 (8%; n = 1/13) cryptococcosis. Most common organ injury was acute respiratory failure (ARF) (71%; n = 49/69) and 41% (n = 28/69) of patients required mechanical ventilation. Twenty (29%; n = 20/69) patients died in the ICU while day-90 mortality reached 55% (n = 35/64). In comparison with survivors, decedents displayed more severe organ dysfunctions (SOFA 7 [5-11] vs. 4 [3-7], p = 0.004) and were more likely to undergo mechanical ventilation (68% vs. 31%, p = 0.010). Sixty-three ibrutinib-treated patients were matched based on age and underlying malignancy with 63 controls receiving conventional chemotherapy from an historic cohort. Despite a higher median number of prior chemotherapy lines (2 [1-2] vs. 0 [0-2]; p < 0.001) and higher rates of fungal [21% vs. 8%, p = 0.001] and viral [17% vs. 5%, p = 0.027] infections in patients receiving ibrutinib, ICU (27% vs. 38%, p = 0.254) and day-90 mortality (52% vs. 48%, p = 0.785) were similar between the two groups. CONCLUSION: In ibrutinib-treated patients, severe infections requiring ICU admission were associated with a dismal prognosis, mostly impacted by initial organ failures. Opportunistic agents should be systematically screened by ICU clinicians in this immunocompromised population.

Clinical spectrum and prognostic impact of cancer in critically ill patients with HIV: a multicentre cohort study.

BACKGROUND: Both AIDS-defining and non-AIDS-defining cancers (ADC/NADC) predispose people living with HIV (PLHIV) to critical illnesses. The objective of this multicentre study was to investigate the prognostic impact of ADC and NADC in PLHIV admitted to the intensive care unit (ICU). METHODS: All PLHIV admitted over the 2015-2020 period in 12 university-affiliated ICUs in France were included in the study cohort. The effect of ADC and NADC on in-hospital mortality (primary study endpoint) was measured through logistic regression with augmented backward elimination of potential independent variables. The association between ADC/NADC and treatment limitation decision (TLD) during the ICU stay (secondary study endpoint) was analysed. One-year mortality in patients discharged alive from the index hospital admission (exploratory study endpoint) was compared between those with ADC, NADC or no cancer. RESULTS: Amongst the 939 included PLHIV (median age, 52 [43-59] years; combination antiretroviral therapy, 74.4%), 97 (10.3%) and 106 (11.3%) presented with an active NADC (mostly lung and intestinal neoplasms) and an active ADC (predominantly AIDS-defining non-Hodgkin lymphoma), respectively. Inaugural admissions were common. Bacterial sepsis and non-infectious neoplasm-related complications accounted for most of admissions in these subgroups. Hospital mortality was 12.4% in patients without cancer, 30.2% in ADC patients and 45.4% in NADC patients (P < 0.0001). NADC (adjusted odds ratio [aOR], 7.00; 95% confidence interval [CI], 4.07-12.05) and ADC (aOR, 3.11; 95% CI 1.76-5.51) were independently associated with in-hospital death after adjustment on severity and frailty markers. The prevalence of TLD was 8.0% in patients without cancer, 17.9% in ADC patients and 33.0% in NADC patients (P < 0.0001)-organ failures and non-neoplastic comorbidities were less often considered in patients with cancer. One-year mortality in survivors of the index hospital admission was 7.8% in patients without cancer, 17.0% in ADC patients and 33.3% in NADC patients (P < 0.0001). CONCLUSIONS: NADC and ADC are equally prevalent, stand as a leading argument for TLD, and strongly predict in-hospital death in the current population of PLHIV requiring ICU admission.

Outcome and factors associated with mortality in patients receiving urgent chemotherapy in the ICU: A retrospective study.

PURPOSE: This study aimed to assess the outcome and factors associated with mortality in patients who received urgent chemotherapy (CT) in the intensive care unit (ICU) in Lyon, France. MATERIAL AND METHODS: A total of 147 adult patients diagnosed with cancer and requiring urgent CT during ICU stay between October 2014 and December 2019 were included in this retrospective study. RESULTS: Hematological cancer was found in 77% of patients, and acute respiratory failure was the leading cause of ICU admission (46.3%). The 6-month mortality rate was 69.4%; patients with solid cancer had a higher risk of mortality. Patients who died within 6 months had a poor performance score and a higher SOFA score at admission. The multivariate analysis showed that solid tumors, sepsis on the day of CT, and SOFA score on the day of CT were associated with 6-month mortality. Additionally, 95% of patients who survived the ICU resumed conventional CT, with a higher likelihood of resuming CT among those with hematological cancer. CONCLUSION: Urgent CT in the ICU is feasible in a specific subset of patients, mainly those with hematological cancer, with resumption of the curative treatment regimen after ICU discharge.

ICU admission for solid cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized the management of cancer. They can induce immune-related adverse events (irAE) leading to intensive care unit (ICU) admission. We aimed to describe irAEs for ICU admissions in solid cancer patients treated with ICIs. METHODS: This prospective multicenter study was conducted in France and Belgium. Adult patients with solid tumor and treated with systemic ICIs within the last 6 months, requiring non-programmed ICU admission were included. Patients admitted for microbiologically documented sepsis were excluded. Imputability of irAEs in ICU admissions was described according to the WHO-UMC classification system at ICU admission and at ICU discharge. The use of immunosuppressant treatment was reported. RESULTS: 115 patients were eligible. Solid tumor was mainly lung cancer (n = 76, 66%) and melanoma (n = 18, 16%). They were mainly treated with an anti-PD-(L)1 alone (n = 110, 96%). Main ICU admission reasons were acute respiratory failure (n = 66, 57%), colitis (n = 14, 13%), and cardiovascular disease (n = 13, 11%). ICU admission was considered "likely" associated with irAE for 48% (n = 55) of patients. Factors independently associated with irAE were a good ECOG performance status (PS) (ECOG-PS of 0 or 1 vs. ECOG-PS of 2-3, odds ratio [OR] = 6.34, 95% confidence interval [95% CI] 2.13-18.90, and OR = 3.66, 95% CI 1.33-10.03, respectively), and a history of irAE (OR = 3.28, 95% CI 1.19-9.01). Steroids were prescribed for 41/55 (75%) patients with ICU admission "likely" related to irAE. Three patients were subsequently treated with immunosuppressants. CONCLUSION: IrAEs accounted for half of ICU admissions in cancer patients receiving ICIs. They could be treated with steroids. Identifying the imputability of irAEs in ICU admissions remains a challenge.

Relationship between immunosuppression and intensive care unit-acquired colonization and infection related to multidrug-resistant bacteria: a prospective multicenter cohort study.

PURPOSE: The impact of immunosuppression on intensive care unit (ICU)-acquired colonization and infection related to multidrug-resistant (MDR) bacteria (ICU-MDR-col and ICU-MDR-inf, respectively) is unknown. METHODS: We carried out an observational prospective cohort study in 8 ICUs in France (all with single-bed rooms and similar organizational characteristics). All consecutive patients with an ICU stay > 48 h were included, regardless of immune status, and followed for 28 days. Patients underwent systematic screening for colonization with MDR bacteria upon admission and every week subsequently. Immunosuppression was defined as active cancer or hematologic malignancy, neutropenia, solid-organ transplant, use of steroids or immunosuppressive drugs, human immunodeficiency virus infection and genetic. The primary endpoint was the incidence rate of a composite outcome including ICU-MDR-col and/or ICU-MDR-inf. RESULTS: 750 patients (65.9% males, median age 65 years) were included, among whom 264 (35.2%) were immunocompromised. Reasons for ICU admission, severity scores and exposure to invasive devices and antibiotics during ICU stay were comparable between groups. After adjustment for center and pre-specified baseline confounders, immunocompromised patients had a lower incidence rate of ICU-MDR-col and/or ICU-MDR-inf (adjusted incidence ratio 0.68, 95% CI 0.52-0.91). When considered separately, the difference was significant for ICU-MDR-col, but not for ICU-MDR-inf. The distribution of MDR bacteria was comparable between groups, with a majority of Enterobacteriacae resistant to third-generation cephalosporins (~ 74%). CONCLUSION: Immunocompromised patients had a significantly lower incidence rate of a composite outcome including ICU-MDR-col and/or ICU-MDR-inf. This finding points to the role of contact precautions and isolation measures, and could have important implications on antibiotic stewardship in this population.

B-cell malignancies and COVID-19: a narrative review.

BACKGROUND: COVID-19 has been extensively characterized in immunocompetent hosts and to a lesser extent in immunocompromised populations. Among the latter, patients treated for B-cell malignancies have immunosuppression generated by B-cell lymphodepletion/aplasia resulting in an increased susceptibility to respiratory virus infections and poor response to vaccination. The consequence is that these patients are likely to develop severe or critical COVID-19. OBJECTIVES: To examine the overall impact of COVID-19 in patients treated for a B-cell malignancy or receiving chimeric antigen receptor T (CAR-T) immunotherapy administered in case of relapsed or refractory disease. SOURCES: We searched in the MEDLINE database to identify relevant studies, trials, reviews, or meta-analyses focusing on SARS-CoV-2 vaccination or COVID-19 management in patients treated for a B-cell malignancy or recipients of CAR-T cell therapy up to 8 July 2022. CONTENT: The epidemiology and outcomes of COVID-19 in patients with B-cell malignancy and CAR-T cell recipients are summarized. Vaccine efficacy in these subgroups is compiled. Considering the successive surges of variants of concern, we propose a critical appraisal of treatment strategies by discussing the use of neutralizing monoclonal antibodies, convalescent plasma therapy, direct-acting antiviral drugs, corticosteroids, and immunomodulators. IMPLICATIONS: For patients with B-cell malignancy, preventive vaccination against SARS-CoV-2 remains essential and the management of COVID-19 includes control of viral replication because of protracted SARS-CoV-2 shedding. Passive immunotherapy (monoclonal neutralizing antibody therapy and convalescent plasma therapy) and direct-active antivirals, such as remdesivir and nirmatrelvir/ritonavir are the best currently available treatments. Real-world data and subgroup analyses in larger trials are warranted to assess COVID-19 therapeutics in B-cell depleted populations.

HLA-DR expression on monocytes and outcome of anti-CD19 CAR T-cell therapy for large B-cell lymphoma.

Despite their unprecedented success in relapsed/refractory (R/R) large B-cell lymphoma (LBCL), anti-CD19 CAR T cells are associated with significant toxicity, and more than half of patients relapse. As monocytes emerged as key players in CAR therapy, we sought to evaluate the evolution of HLA-DR expression on monocytes (mHLA-DR) before and after commercial anti-CD19 CAR T-cell infusion in a large cohort (n = 103) of patients with R/R LBCL and its association with adverse events and treatment response. Cy-Flu-based lymphodepletion (LD) upregulated mHLA-DR in 79% of the cases, whereas in 2l% of cases (15 patients), the mHLA-DR level decreased after LD, and this decrease was associated with poorer outcome. Low mHLA-DR at day minus 7 (D-7) (<13 500 antibodies per cell) before CAR T-cell infusion correlated with older age, poorer performance status, higher tumor burden, and elevated inflammatory markers. With a median follow-up of 7.4 months, patients with low mHLA-DR D-7 exhibited a poorer duration of response and survival than the higher mHLA-DR D-7 group. For toxicity management, tocilizumab was more frequently used in the low-mHLA-DR D-7 group. These data suggest that monocyte dysregulation before LD, characterized by the downregulation of mHLA-DR, correlates with an inflammatory and immunosuppressive tumor environment and is associated with failure of anti-CD19 CAR T cells in patients with R/R LBCL. Modulation of these myeloid cells represents a promising field for improving CAR therapy.

Tracheal stent aspergillosis occurring after aortic allograft of the trachea.

BACKGROUND: Aspergillosis is a fungal infection with many clinical forms. Invasive aspergillosis is the most widely known severe manifestation, but other forms can need intensive care. AIM: Our purpose is to report a case of tracheal aspergilloma and provide a review of the literature concerning endobronchial aspergillus. METHOD: We report a case of tracheal aspergilloma causing tracheal obstruction in a patient admitted in the ICU for respiratory distress. The aspergilloma occurred in a tracheal stent implanted during tracheal allograft for tracheal cancer. A combination of local and systemic antifungal was used with successful result.

The burden of SARS-CoV-2 in patients receiving chimeric antigen receptor T cell immunotherapy: everything to lose.

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell immunotherapy has revolutionized the prognosis of refractory or relapsed B-cell malignancies. CAR-T cell recipients have immunosuppression generated by B-cell aplasia, leading to a higher susceptibility to respiratory virus infections and poor response to vaccination. AREAS COVERED: This review focuses on the challenge posed by B-cell targeted immunotherapies: managing long-lasting B-cell impairment during the successive surges of a deadly viral pandemic. We restricted this report to data regarding vaccine efficacy in CAR-T cell recipients, outcomes after developing COVID-19 and specificities of treatment management. We searched in MEDLINE database to identify relevant studies until 31 March 2022. EXPERT OPINION: Among available observational studies, the pooled mortality rate reached 40% in CAR-T cell recipients infected by SARS-CoV-2. Additionally, vaccine responses seem to be widely impaired in recipients (seroconversion 20%, T-cell response 50%). In this setting of B-cell depletion, passive immunotherapy is the backbone of treatment. Convalescent plasma therapy has proven to be a highly effective curative treatment with rare adverse events. Neutralizing monoclonal antibodies could be used as pre-exposure prophylaxis or early treatment but their neutralizing activity is constantly challenged by new variants. In order to reduce viral replication, direct-acting antiviral drugs should be considered.

Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial.

BACKGROUND: The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. OBJECTIVES: To estimate the effect of remdesivir in blocking viral replication. METHODS: We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). RESULTS: In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5-3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0-1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8-25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9-4.5 days). CONCLUSIONS: Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.

A retrospective comparison of COVID-19 and seasonal influenza mortality and outcomes in the ICUs of a French university hospital.

BACKGROUND: SARS-Cov-2 (COVID-19) has become a major worldwide health concern since its appearance in China at the end of 2019. OBJECTIVE: To evaluate the intrinsic mortality and burden of COVID-19 and seasonal influenza pneumonia in ICUs in the city of Lyon, France. DESIGN: A retrospective study. SETTING: Six ICUs in a single institution in Lyon, France. PATIENTS: Consecutive patients admitted to an ICU with SARS-CoV-2 pneumonia from 27 February to 4 April 2020 (COVID-19 group) and seasonal influenza pneumonia from 1 November 2015 to 30 April 2019 (influenza group). A total of 350 patients were included in the COVID-19 group (18 refused to consent) and 325 in the influenza group (one refused to consent). Diagnosis was confirmed by RT-PCR. Follow-up was completed on 1 April 2021. MAIN OUTCOMES AND MEASURES: Differences in 90-day adjusted-mortality between the COVID-19 and influenza groups were evaluated using a multivariable Cox proportional hazards model. RESULTS: COVID-19 patients were younger, mostly men and had a higher median BMI, and comorbidities, including immunosuppressive condition or respiratory history were less frequent. In univariate analysis, no significant differences were observed between the two groups regarding in-ICU mortality, 30, 60 and 90-day mortality. After Cox modelling adjusted on age, sex, BMI, cancer, sepsis-related organ failure assessment (SOFA) score, simplified acute physiology score SAPS II score, chronic obstructive pulmonary disease and myocardial infarction, the probability of death associated with COVID-19 was significantly higher in comparison to seasonal influenza [hazard ratio 1.57, 95% CI (1.14 to 2.17); P = 0.006]. The clinical course and morbidity profile of both groups was markedly different; COVID-19 patients had less severe illness at admission (SAPS II score, 37 [28 to 48] vs. 48 [39 to 61], P < 0.001 and SOFA score, 4 [2 to 8] vs. 8 [5 to 11], P < 0.001), but the disease was more severe considering ICU length of stay, duration of mechanical ventilation, PEEP level and prone positioning requirement. CONCLUSION: After ICU admission, COVID-19 was associated with an increased risk of death compared with seasonal influenza. Patient characteristics, clinical course and morbidity profile of these diseases is markedly different.

CAR-T cell: Toxicities issues: Mechanisms and clinical management.

CAR-T cells are modified T cells expressing a chimeric antigen receptor targeting a specific antigen. They have revolutionized the treatment of B cell malignancies (aggressive lymphomas, B-ALL), and this has raised hopes for application in many other pathologies (myeloma, AML, solid tumors, etc.). However, these therapies are associated with novel and specific toxicities (cytokine release syndrome and neurotoxicity). These complications, although mostly managed in a conventional hospitalization unit, can sometimes be life threatening, leading to admission of patients to the intensive care unit. Management relies mainly on anti-IL6R (tocilizumab) and corticosteroids. However, the optimal treatment regimen is still a matter of debate, and the management of the most severe forms is even less well codified. In addition to CRS and ICANS, infections, cytopenia and hypogammaglobulinemia are other frequent complications. This article reviews the mechanisms, risk factors, clinical presentation, and management of these toxicities.

Prognostic Impact of 18F-FDG PET/CT in Patients With Aggressive B-Cell Lymphoma Treated With Anti-CD19 Chimeric Antigen Receptor T Cells.

PURPOSE OF THE REPORT: We aimed to evaluate the role of 18F-FDG PET/CT in predicting patient outcome following chimeric antigen receptor T (CAR T) cells infusion in aggressive B-cell lymphoma. METHODS: 18F-FDG PET/CT data before leukapheresis, before CAR T-cell infusion and 1 month (M1) after CAR T-cell infusion, from 72 patients were retrospectively analyzed. SUVmax, total lesion glycolysis (TLG), metabolic tumor volume (MTV), and parameters describing tumor kinetics were calculated for each 18F-FDG PET/CT performed. The aim was to evaluate the prognostic value of 18F-FDG PET/CT metabolic parameters for predicting progression-free survival (PFS) and overall survival (OS) following CAR T-cell therapy. RESULTS: Regarding PFS, ∆MTVpre-CAR and ∆TLGpre-CAR were found to be more discriminating compared with metabolic parameters at preinfusion. Median PFS in patients with a ∆MTVpre-CAR of less than 300% was 6.8 months (95% confidence interval [CI], 2.8 months to not reached) compared with 2.8 months (95% CI, 0.9-3.0 months) for those with a value of 300% or greater (P = 0.004). Likewise, median PFS in patients with ∆TLGpre-CAR of less than 420% was 6.8 months (95% CI, 2.8 months to not reached) compared with 2.7 months (95% CI, 1.3-3.0 months) for those with a value of 420% or greater (P = 0.0148). Regarding OS, metabolic parameters at M1 were strongly associated with subsequent outcome. SUVmax at M1 with a cutoff value of 14 was the most predictive parameter in multivariate analysis, outweighing other clinicobiological variables (P < 0.0001). CONCLUSIONS: Disease metabolic volume kinetics before infusion of CAR T cells seems to be superior to initial tumor bulk itself for predicting PFS. For OS, SUVmax at M1 might adequately segregate patients with different prognosis.

BMI and pneumonia outcomes in critically ill covid-19 patients: An international multicenter study.

OBJECTIVE: Previous studies have unveiled a relationship between the severity of coronavirus disease 2019 (COVID-19) pneumonia and obesity. The aims of this multicenter retrospective cohort study were to disentangle the association of BMI and associated metabolic risk factors (diabetes, hypertension, hyperlipidemia, and current smoking status) in critically ill patients with COVID-19. METHODS: Patients admitted to intensive care units for COVID-19 in 21 centers (in Europe, Israel, and the United States) were enrolled in this study between February 19, 2020, and May 19, 2020. Primary and secondary outcomes were the need for invasive mechanical ventilation (IMV) and 28-day mortality, respectively. RESULTS: A total of 1,461 patients were enrolled; the median (interquartile range) age was 64 years (40.9-72.0); 73.2% of patients were male; the median BMI was 28.1 kg/m2 (25.4-32.3); a total of 1,080 patients (73.9%) required IMV; and the 28-day mortality estimate was 36.1% (95% CI: 33.0-39.5). An adjusted mixed logistic regression model showed a significant linear relationship between BMI and IMV: odds ratio = 1.27 (95% CI: 1.12-1.45) per 5 kg/m2 . An adjusted Cox proportional hazards regression model showed a significant association between BMI and mortality, which was increased only in obesity class III (≥40; hazard ratio = 1.68 [95% CI: 1.06-2.64]). CONCLUSIONS: In critically ill COVID-19 patients, a linear association between BMI and the need for IMV, independent of other metabolic risk factors, and a nonlinear association between BMI and mortality risk were observed.

Outcomes in patients treated with chimeric antigen receptor T-cell therapy who were admitted to intensive care (CARTTAS): an international, multicentre, observational cohort study.

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 Réanimation Onco-Hématologique.

Sinusoidal Obstruction Syndrome in Critically Ill Patients in the Era of Defibrotide: A Retrospective Multicenter Study.

Sinusoidal obstruction syndrome (SOS) is a life-threatening liver complication of high- dose chemotherapy. Defibrotide is the only available therapeutic option approved for SOS. The prognosis of SOS in patients requiring intensive care unit (ICU) admission remains unknown. The primary objective of this study was to assess the outcome of SOS patients in ICU. This retrospective study was conducted between 2007 and 2019 in 13 French ICUs. Seventy-one critically ill adult patients with SOS defined according to European Society for Blood and Marrow Transplantation criteria and treated with defibrotide were included. The main reasons for ICU admission were respiratory failure and acute kidney injury. Mechanical ventilation, vasopressors, and renal replacement therapy were required in 59%, 52%, and 49% of patients, respectively. Twenty-three percent of patients experienced a bleeding event during defibrotide treatment. Hospital mortality was 54%, mainly related to multiorgan failure. Older age (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00 to 1.04), mechanical ventilation (HR, 1.99; 95% CI, 1.00 to 3.99), renal replacement therapy (HR, 2.55; 95% CI, 1.32 to 4.91) were independent predictors of hospital mortality. Defibrotide prophylaxis (HR, 0.35; 95% CI, 0.13 to 0.92) was associated with better outcomes. Critically ill patients with SOS have a high mortality rate in the ICU, especially if organ support is required. Additional studies assessing the impact of defibrotide prophylaxis are warranted.

Description of neurotoxicity in a series of patients treated with CAR T-cell therapy.

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1-2 severity and 34% had grade 3-4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3-4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.