Critical care management of chimeric antigen receptor T-cell therapy recipients.

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies. The development of CAR T-cell therapy represents a prime example for the successful bench-to-bedside translation of advances in immunology and cellular therapy into clinical practice. The currently available CAR T-cell products have shown high response rates and long-term remissions in patients with relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory lymphoma. However, CAR T-cell therapy can induce severe life-threatening toxicities such as cytokine release syndrome, neurotoxicity, or infection, which require rapid and aggressive medical treatment in the intensive care unit setting. In this review, the authors provide an overview of the state-of-the-art in the clinical management of severe life-threatening events in CAR T-cell recipients. Furthermore, key challenges that have to be overcome to maximize the safety of CAR T cells are discussed.

How I manage acute respiratory failure in patients with hematological malignancies.

ABSTRACT: Acute respiratory failure (ARF) is common in patients with hematological malignancies notably those with acute leukemia, myelodysplastic syndrome, or allogeneic stem cell transplantation. ARF is the leading reason for intensive care unit (ICU) admission, with a 35% case fatality rate. Failure to identify the ARF cause is associated with mortality. A prompt, well-designed diagnostic workup is crucial. The investigations are chosen according to pretest diagnostic probabilities, estimated by the DIRECT approach: D stands for delay, or time since diagnosis; I for pattern of immune deficiency; R and T for radiological evaluation; E refers to clinical experience, and C to the clinical picture. Thorough familiarity with rapid diagnostic tests helps to decrease the use of bronchoscopy with bronchoalveolar lavage, which can cause respiratory status deterioration in those patients with hypoxemia. A prompt etiological diagnosis shortens the time on unnecessary empirical treatments, decreasing iatrogenic harm and costs. High-quality collaboration between intensivists and hematologists and all crossdisciplinary health care workers is paramount. All oxygen delivery systems should be considered to minimize invasive mechanical ventilation. Treatment of the malignancy is started or continued in the ICU under the guidance of the hematologists. The goal is to use the ICU as a bridge to recovery, with the patient returning to the hematology ward in sufficiently good clinical condition to receive optimal anticancer treatment.

High Airway Occlusion Pressure Is Associated with Dyspnea and Increased Mortality in Critically Ill Mechanically Ventilated Patients.

Rationale: Airway occlusion pressure at 100 ms (P0.1) reflects central respiratory drive. Objectives: We aimed to assess factors associated with P0.1 and whether an abnormally low or high P0.1 value is associated with higher mortality and longer duration of mechanical ventilation (MV). Methods: We performed a secondary analysis of a prospective cohort study conducted in 10 ICUs in France to evaluate dyspnea in communicative MV patients. In patients intubated for more than 24 hours, P0.1 was measured with dyspnea as soon as patients could communicate and the next day. Measurements and Main Results: Among 260 patients assessed after a median time of ventilation of 4 days, P0.1 was 1.9 (1-3.5) cm H2O at enrollment, 24% had P0.1 values >3.5 cm H2O, 37% had P0.1 values between 1.5 and 3.5 cm H2O, and 39% had P0.1 values <1.5 cm H2O. In multivariable linear regression, independent factors associated with P0.1 were the presence of dyspnea (P = 0.037), respiratory rate (P < 0.001), and PaO2 (P = 0.008). Ninety-day mortality was 33% in patients with P0.1 > 3.5 cm H2O versus 19% in those with P0.1 between 1.5 and 3.5 cm H2O and 17% in those with P0.1 < 1.5 cm H2O (P = 0.046). After adjustment for the main risk factors, P0.1 was associated with 90-day mortality (hazard ratio per 1 cm H2O, 1.19 [95% confidence interval, 1.04-1.37]; P = 0.011). P0.1 was also independently associated with a longer duration of MV (hazard ratio per 1 cm H2O, 1.10 [95% confidence interval, 1.02-1.19]; P = 0.016). Conclusions: In patients receiving invasive MV, abnormally high P0.1 values may suggest dyspnea and are associated with higher mortality and prolonged duration of MV.

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.

Resilience and Mental-Health Symptoms in ICU Healthcare Professionals Facing Repeated COVID-19 Waves.

Rationale: Psychological resilience (the ability to thrive in adversity) may protect against mental-health symptoms in healthcare professionals during coronavirus disease (COVID-19) waves. Objectives: To identify determinants of resilience in ICU staff members. Methods: In this cross-sectional survey in 21 French ICUs, staff members completed the 10-item Connor-Davidson Resilience Scale, Hospital Anxiety and Depression Scale, and Impact of Event Scale-Revised (for post-traumatic stress disorder [PTSD]). Factors independently associated with resilience were identified. Measurements and Main Results: The response rate was 73.1% (950 of 1,300). The median 10-item Connor-Davidson Resilience Scale score was 29 (interquartile range, 25-32). Symptoms of anxiety, depression, and PTSD were present in 61%, 39%, and 36% of staff members, respectively. Distress associated with the COVID-19 infodemic was correlated with symptoms of depression and PTSD. More resilient respondents less often had symptoms of anxiety, depression, and PTSD. Greater resilience was independently associated with male sex, having provided intensive care during the early waves, having managed more than 50 patients with COVID-19, and, compared with earlier waves, working longer hours, having greater motivation, and more often involving families in end-of-life decisions. Independent risk factors for lower resilience were having managed more than 10 patients who died of COVID-19, having felt frightened or isolated, and greater distress from the COVID-19 infodemic. Conclusions: This study identifies modifiable determinants of resilience among ICU staff members. Longitudinal studies are needed to determine whether prior resilience decreases the risk of mental ill health during subsequent challenges. Hospital and ICU managers, for whom preserving mental well-being among staff members is a key duty, should pay careful attention to resilience.

Critically Ill Patients with Visceral Nocardia Infection, France and Belgium, 2004-2023.

We studied 50 patients with invasive nocardiosis treated during 2004-2023 in intensive care centers in France and Belgium. Most (65%) died in the intensive care unit or in the year after admission. Nocardia infections should be included in the differential diagnoses for patients in the intensive care setting.

Dyspnoea in acutely ill mechanically ventilated adult patients: an ERS/ESICM statement.

This statement outlines a review of the literature and current practice concerning the prevalence, clinical significance, diagnosis and management of dyspnoea in critically ill, mechanically ventilated adult patients. It covers the definition, pathophysiology, epidemiology, short- and middle-term impact, detection and quantification, and prevention and treatment of dyspnoea. It represents a collaboration of the European Respiratory Society and the European Society of Intensive Care Medicine. Dyspnoea ranks among the most distressing experiences that human beings can endure. Approximately 40% of patients undergoing invasive mechanical ventilation in the intensive care unit (ICU) report dyspnoea, with an average intensity of 45 mm on a visual analogue scale from 0 to 100 mm. Although it shares many similarities with pain, dyspnoea can be far worse than pain in that it summons a primal fear response. As such, it merits universal and specific consideration. Dyspnoea must be identified, prevented and relieved in every patient. In the ICU, mechanically ventilated patients are at high risk of experiencing breathing difficulties because of their physiological status and, in some instances, because of mechanical ventilation itself. At the same time, mechanically ventilated patients have barriers to signalling their distress. Addressing this major clinical challenge mandates teaching and training, and involves ICU caregivers and patients. This is even more important because, as opposed to pain which has become a universal healthcare concern, very little attention has been paid to the identification and management of respiratory suffering in mechanically ventilated ICU patients.

Typology of ICU-Healthcare Providers Who Delayed or Declined COVID-19 Vaccination.

OBJECTIVES: To assess COVID-19 vaccination rates in ICU-healthcare providers (HCPs) in France and to identify the typology of those who delayed or declined vaccination. DESIGN: Cross-sectional study. SETTING: Twenty-one ICUs in France. SUBJECTS: Members of the nursing and medical staff and other allied professionals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six hundred ninety-six of the 950 respondents (73.3%) had undergone a full vaccination schedule. Other HCPs either declined vaccination ( n = 112) or delayed vaccination until it became mandatory ( n = 142). Factors independently associated with full vaccination were age older than 50 years (odds ratio, 0.25 [95% CI, 0.12-0.51]), more than 5 years of ICU experience (0.66 [0.47-0.93]), increasing working time during the surge (0.94 [0.88-1.00]), and spending time with the family (0.92 [0.85-0.99]). Conversely, being a nurse (1.94 [1.25-2.99]) or a nurse assistant (2.77 [1.62-4.73]), and feeling not supported by hospital and ICU directors (1.49 [1.01-2.20]) was independently associated with not being vaccinated. CONCLUSIONS: These results are important to take into account to better implement vaccination strategies in HCPs for existing or future pandemics.

Contemplating dengue: the thinker's reflection on symptoms.

In this image, the autors reinterprate "The Thinker" from Auguste Rodin to transfer knowledge about dengue fever, which can range from flu-like illness to severe hemorrhagic fever. By fostering awareness and understanding of dengue fever, we strive to empower individuals and communities in the ongoing fight against dengue and other infectious threats.

Incidence, risk factors and outcomes of nosocomial infection in adult patients supported by extracorporeal membrane oxygenation: a systematic review and meta-analysis.

BACKGROUND: An increasing number of patients requires extracorporeal membrane oxygenation (ECMO) for life support. This supportive modality is associated with nosocomial infections (NIs). This systematic review and meta-analysis aim to assess the incidence and risk factors of NIs in adult. METHODS: We searched PubMed, Scopus, Web of Science, and ProQuest databases up to 2022. The primary endpoint was incidence of NI. Secondary endpoints included time to infection, source of infection, ECMO duration, Intensive care and hospital length of stay (LOS), ECMO survival and overall survival. Incidence of NI was reported as pooled proportions and 95% confidence intervals (CIs), while dichotomous outcomes were presented as risk ratios (RR) as the effective index and 95% CIs using a random-effects model. RESULTS: Among the 4,733 adult patients who received ECMO support in the 30 included studies, 1,249 ECMO-related NIs per 1000 ECMO-days was observed. The pooled incidence of NIs across 18 studies involving 3424 patients was 26% (95% CI 14-38%).Ventilator-associated pneumonia (VAP) and bloodstream infections (BSI) were the most common NI sources. Infected patients had lower ECMO survival and overall survival rates compared to non-infected patients, with risk ratio values of 0.84 (95% CI 0.74-0.96, P = 0.01) and 0.80 (95% CI 0.71-0.90, P < 0.001), respectively. CONCLUSION: Results showed that 16% and 20% lower of ECMO survival and overall survival in patients with NI than patients without NI, respectively. However, NI increased the risk of in-hospital mortality by 37% in infected patients compared with non-infected patients. In addition, this study identified the significant positive correlation between ECMO duration and ECMO-related NI.

Septic shock in the immunocompromised cancer patient: a narrative review.

Immunosuppressed patients, particularly those with cancer, represent a momentous and increasing portion of the population, especially as cancer incidence rises with population growth and aging. These patients are at a heightened risk of developing severe infections, including sepsis and septic shock, due to multiple immunologic defects such as neutropenia, lymphopenia, and T and B-cell impairment. The diverse and complex nature of these immunologic profiles, compounded by the concomitant use of immunosuppressive therapies (e.g., corticosteroids, cytotoxic drugs, and immunotherapy), superimposed by the breakage of natural protective barriers (e.g., mucosal damage, chronic indwelling catheters, and alterations of anatomical structures), increases the risk of various infections. These and other conditions that mimic sepsis pose substantial diagnostic and therapeutic challenges. Factors that elevate the risk of progression to septic shock in these patients include advanced age, pre-existing comorbidities, frailty, type of cancer, the severity of immunosuppression, hypoalbuminemia, hypophosphatemia, Gram-negative bacteremia, and type and timing of responses to initial treatment. The management of vulnerable cancer patients with sepsis or septic shock varies due to biased clinical practices that may result in delayed access to intensive care and worse outcomes. While septic shock is typically associated with poor outcomes in patients with malignancies, survival has significantly improved over time. Therefore, understanding and addressing the unique needs of cancer patients through a new paradigm, which includes the integration of innovative technologies into our healthcare system (e.g., wireless technologies, medical informatics, precision medicine), targeted management strategies, and robust clinical practices, including early identification and diagnosis, coupled with prompt admission to high-level care facilities that promote a multidisciplinary approach, is crucial for improving their prognosis and overall survival rates.

Clinical characteristics and outcomes of immunocompromised critically ill patients with cytomegalovirus end-organ disease: a multicenter retrospective cohort study.

BACKGROUND: Cytomegalovirus (CMV) infection in patients with cellular immune deficiencies is associated with significant morbidity and mortality. However, data on CMV end-organ disease (CMV-EOD) in critically ill, immunocompromised patients are scarce. Our objective here was to describe the clinical characteristics and outcomes of CMV-EOD in this population. METHODS: We conducted a multicenter, international, retrospective, observational study in adults who had CMV-EOD and were admitted to any of 18 intensive care units (ICUs) in France, Israel, and Spain in January 2010-December 2021. Patients with AIDS were excluded. We collected the clinical characteristics and outcomes of each patient. Survivors and non-survivors were compared, and multivariate analysis was performed to identify risk factors for hospital mortality. RESULTS: We studied 185 patients, including 80 (43.2%) with hematologic malignancies, 55 (29.7%) with solid organ transplantation, 31 (16.8%) on immunosuppressants, 16 (8.6%) with solid malignancies, and 3 (1.6%) with primary immunodeficiencies. The most common CMV-EOD was pneumonia (n = 115, [62.2%] including 55 [47.8%] with a respiratory co-pathogen), followed by CMV gastrointestinal disease (n = 64 [34.6%]). More than one organ was involved in 16 (8.8%) patients. Histopathological evidence was obtained for 10/115 (8.7%) patients with pneumonia and 43/64 (67.2%) with GI disease. Other opportunistic infections were diagnosed in 69 (37.3%) patients. Hospital mortality was 61.4% overall and was significantly higher in the group with hematologic malignancies (75% vs. 51%, P = 0.001). Factors independently associated with higher hospital mortality were hematologic malignancy with active graft-versus-host disease (OR 5.02; 95% CI 1.15-27.30), CMV pneumonia (OR 2.57; 95% CI 1.13-6.03), lymphocytes < 0.30 × 109/L at diagnosis of CMV-EOD (OR 2.40; 95% CI 1.05-5.69), worse SOFA score at ICU admission (OR 1.18; 95% CI 1.04-1.35), and older age (OR 1.04; 95% CI 1.01-1.07). CONCLUSIONS: Mortality was high in critically ill, immunocompromised patients with CMV-EOD and varied considerably with the cause of immunodeficiency and organ involved by CMV. Three of the four independent risk factors identified here are also known to be associated with higher mortality in the absence of CMV-EOD. CMV pneumonia was rarely proven by histopathology and was the most severe CMV-EOD.

Single-drug versus combination antimicrobial therapy in critically ill patients with hospital-acquired pneumonia and ventilator-associated pneumonia due to Gram-negative pathogens: a multicenter retrospective cohort study.

KEY MESSAGES: In this study including 391 critically ill patients with nosocomial pneumonia due to Gram-negative pathogens, combination therapy was not associated with a reduced hazard of death at Day 28 or a greater likelihood of clinical cure at Day 14. No over-risk of AKI was observed in patients receiving combination therapy. BACKGROUND: The benefits and harms of combination antimicrobial therapy remain controversial in critically ill patients with hospital-acquired pneumonia (HAP), ventilated HAP (vHAP) or ventilator-associated pneumonia (VAP) involving Gram-negative bacteria. METHODS: We included all patients in the prospective multicenter OutcomeRea database with a first HAP, vHAP or VAP due to a single Gram-negative bacterium and treated with initial adequate single-drug or combination therapy. The primary endpoint was Day-28 all-cause mortality. Secondary endpoints were clinical cure rate at Day 14 and a composite outcome of death or treatment-emergent acute kidney injury (AKI) at Day 7. The average effects of combination therapy on the study endpoints were investigated through inverse probability of treatment-weighted regression and multivariable regression models. Subgroups analyses were performed according to the resistance phenotype of the causative pathogens (multidrug-resistant or not), the pivotal (carbapenems or others) and companion (aminoglycosides/polymyxins or others) drug classes, the duration of combination therapy (< 3 or ≥ 3 days), the SOFA score value at pneumonia onset (< 7 or ≥ 7 points), and in patients with pneumonia due to non-fermenting Gram-negative bacteria, pneumonia-related bloodstream infection, or septic shock. RESULTS: Among the 391 included patients, 151 (38.6%) received single-drug therapy and 240 (61.4%) received combination therapy. VAP (overall, 67.3%), vHAP (16.4%) and HAP (16.4%) were equally distributed in the two groups. All-cause mortality rates at Day 28 (overall, 31.2%), clinical cure rate at Day 14 (43.7%) and the rate of death or AKI at Day 7 (41.2%) did not significantly differ between the groups. In inverse probability of treatment-weighted analyses, combination therapy was not independently associated with the likelihood of all-cause death at Day 28 (adjusted odd ratio [aOR], 1.14; 95% confidence interval [CI] 0.73-1.77; P = 0.56), clinical cure at Day 14 (aOR, 0.79; 95% CI 0.53-1.20; P = 0.27) or death or AKI at Day 7 (aOR, 1.07; 95% CI 0.71-1.63; P = 0.73). Multivariable regression models and subgroup analyses provided similar results. CONCLUSIONS: Initial combination therapy exerts no independent impact on Day-28 mortality, clinical cure rate at Day 14, and the hazard of death or AKI at Day 7 in critically ill patients with mono-bacterial HAP, vHAP or VAP due to Gram-negative bacteria.

Severe Community-Acquired Pneumonia in Immunocompromised Patients.

Due to higher survival rates with good quality of life, related to new treatments in the fields of oncology, hematology, and transplantation, the number of immunocompromised patients is increasing. But these patients are at high risk of intensive care unit admission because of numerous complications. Acute respiratory failure due to severe community-acquired pneumonia is one of the leading causes of admission. In this setting, the need for invasive mechanical ventilation is up to 60%, associated with a high hospital mortality rate of around 40 to 50%. A wide range of pathogens according to the reason of immunosuppression is associated with severe pneumonia in those patients: documented bacterial pneumonia represents a third of cases, viral and fungal pneumonia both account for up to 15% of cases. For patients with an undetermined etiology despite comprehensive diagnostic workup, the hospital mortality rate is very high. Thus, a standardized diagnosis strategy should be defined to increase the diagnosis rate and prescribe the appropriate treatment. This review focuses on the benefit-to-risk ratio of invasive or noninvasive strategies, in the era of omics, for the management of critically ill immunocompromised patients with severe pneumonia in terms of diagnosis and oxygenation.

Platelet transfusions in adult thrombocytopenic ICU patients: Protocol for a sub-study of the PLOT-ICU cohort.

INTRODUCTION: Platelet transfusions are frequently used in intensive care unit (ICU) patients, but contemporary epidemiological data are sparse. We aim to present contemporary international data on the use of platelet transfusions in adult ICU patients with thrombocytopenia. METHODS: This is a protocol and statistical analysis plan for a post hoc sub-study of 504 thrombocytopenic patients from the 'Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)'. The primary outcome will be the number of patients receiving platelet transfusion in the ICU reported according to the type of product received (apheresis-derived versus pooled whole-blood-derived transfusions). Secondary platelet transfusion outcomes will include platelet transfusion volumes; timing of platelet transfusion; approach to platelet transfusion dosing (fixed dosing versus weight-based dosing) and platelet count increments for prophylactic transfusions. Secondary clinical outcomes will include the number of patients receiving red blood cell- and plasma transfusions during ICU stay; the number of patients who bled in the ICU, the number of patients who had a new thrombosis in the ICU, and the number of patients who died. The duration of follow-up was 90 days. Baseline characteristics and secondary clinical outcomes will be stratified according to platelet transfusion status in the ICU and severity of thrombocytopenia. Data will be presented descriptively. CONCLUSIONS: The outlined study will provide detailed epidemiological data on the use of platelet transfusions in adult ICU patients with thrombocytopenia using data from the large international PLOT-ICU cohort study. The findings will inform the design of future randomised trials evaluating platelet transfusions in ICU patients.

Platelet transfusions in adult ICU patients with thrombocytopenia: A sub-study of the PLOT-ICU inception cohort study.

BACKGROUND: Platelet transfusions are frequently used in the intensive care unit (ICU), but current practices including used product types, volumes, doses and effects are unknown. STUDY DESIGN AND METHODS: Sub-study of the inception cohort study 'Thrombocytopenia and Platelet Transfusions in the ICU (PLOT-ICU)', including acutely admitted, adult ICU patients with thrombocytopenia (platelet count <150 × 109/L). The primary outcome was the number of patients receiving platelet transfusion in ICU by product type. Secondary outcomes included platelet transfusion details, platelet increments, bleeding, other transfusions and mortality. RESULTS: Amongst 504 patients with thrombocytopenia from 43 hospitals in 10 countries in Europe and the United States, 20.8% received 565 platelet transfusions; 61.0% received pooled products, 21.9% received apheresis products and 17.1% received both with a median of 2 (interquartile range 1-4) days from admission to first transfusion. The median volume per transfusion was 253 mL (180-308 mL) and pooled products accounted for 59.1% of transfusions, however, this varied across countries. Most centres (73.8%) used fixed dosing (medians ranging from 2.0 to 3.5 × 1011 platelets/transfusion) whilst some (mainly in France) used weight-based dosing (ranging from 0.5 to 0.7 × 1011 platelets per 10 kg body weight). The median platelet count increment for a single prophylactic platelet transfusion was 2 (-1 to 8) × 109/L. Outcomes of patients with thrombocytopenia who did and did not receive platelet transfusions varied. CONCLUSIONS: Among acutely admitted, adult ICU patients with thrombocytopenia, 20.8% received platelet transfusions in ICU of whom most received pooled products, but considerable variation was observed in product type, volumes and doses across countries. Prophylactic platelet transfusions were associated with limited increases in platelet counts.

A three-step support strategy for relatives of patients dying in the intensive care unit: a cluster randomised trial.

BACKGROUND: In relatives of patients dying in intensive care units (ICUs), inadequate team support can increase the prevalence of prolonged grief and other psychological harm. We aimed to evaluate whether a proactive communication and support intervention would improve relatives' outcomes. METHODS: We undertook a prospective, multicentre, cluster randomised controlled trial in 34 ICUs in France, to compare standard care with a physician-driven, nurse-aided, three-step support strategy for families throughout the dying process, following a decision to withdraw or withhold life support. Inclusion criteria were relatives of patients older than 18 years with an ICU length of stay 2 days or longer. Participating ICUs were randomly assigned (1:1 ratio) into an intervention cluster and a control cluster. The randomisation scheme was generated centrally by a statistician not otherwise involved in the study, using permutation blocks of non-released size. In the intervention group, three meetings were held with relatives: a family conference to prepare the relatives for the imminent death, an ICU-room visit to provide active support, and a meeting after the patient's death to offer condolences and closure. ICUs randomly assigned to the control group applied their best standard of care in terms of support and communication with relatives of dying patients. The primary endpoint was the proportion of relatives with prolonged grief (measured with PG-13, score ≥30) 6 months after the death. Analysis was by intention to treat, with the bereaved relatives as the unit of observation. The study is registered with ClinicalTrials.gov, NCT02955992. FINDINGS: Between Feb 23, 2017, and Oct 8, 2019, we enrolled 484 relatives of ICU patients to the intervention group and 391 to the control group. 379 (78%) relatives in the intervention group and 309 (79%) in the control group completed the 6-month interview to measure the primary endpoint. The intervention significantly reduced the number of relatives with prolonged grief symptoms (66 [21%] vs 57 [15%]; p=0·035) and the median PG-13 score was significantly lower in the intervention group than in the control group (19 [IQR 14-26] vs 21 [15-29], mean difference 2·5, 95% CI 1·04-3·95). INTERPRETATION: Among relatives of patients dying in the ICU, a physician-driven, nurse-aided, three-step support strategy significantly reduced prolonged grief symptoms. FUNDING: French Ministry of Health.

High-Dose Steroids for Nonresolving Acute Respiratory Distress Syndrome in Critically Ill COVID-19 Patients Treated With Dexamethasone: A Multicenter Cohort Study.

OBJECTIVES: To determine the impact of high doses of corticosteroids (HDCT) in critically ill COVID-19 patients with nonresolving acute respiratory distress syndrome (ARDS) who had been previously treated with dexamethasone as a standard of care. DESIGN: Prospective observational cohort study. Eligible patients presented nonresolving ARDS related to severe acute respiratory syndrome coronavirus 2 infection and had received initial treatment with dexamethasone. We compared patients who had received or not HDCT during ICU stay, consisting of greater than or equal to 1 mg/kg of methylprednisolone or equivalent for treatment of nonresolving ARDS. The primary outcome was 90-day mortality. We assessed the impact of HDCT on 90-day mortality using univariable and multivariable Cox regression analysis. Further adjustment for confounding variables was performed using overlap weighting propensity score. The association between HDCT and the risk of ventilator-associated pneumonia was estimated using multivariable cause-specific Cox proportional hazard model adjusting for pre-specified confounders. SETTING: We included consecutive patients admitted in 11 ICUs of Great Paris area from September 2020 to February 2021. PATIENTS: Three hundred eighty-three patients were included (59 in the HDCT group, 324 in the no HDCT group). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At day 90, 30 of 59 patients (51%) in the HDCT group and 116 of 324 patients (35.8%) in the no HDCT group had died. HDCT was significantly associated with 90-day mortality in unadjusted (hazard ratio [HR], 1.60; 95% CI, 1.04-2.47; p = 0.033) and adjusted analysis with overlap weighting (adjusted HR, 1.65; 95% CI, 1.03-2.63; p = 0.036). HDCT was not associated with an increased risk of ventilator-associated pneumonia (adjusted cause-specific HR, 0.42; 95% CI, 0.15-1.16; p = 0.09). CONCLUSIONS: In critically ill COVID-19 patients with nonresolving ARDS, HDCT result in a higher 90-day mortality.

Respiratory torque teno virus load at emergency department visit predicts intensive care unit admission of SARS-CoV-2 infected patients.

Accurate prediction of COVID-19 severity remains a challenge. Torque teno virus (TTV), recognized as a surrogate marker of functional immunity in solid organ transplant recipients, holds the potential for assessing infection outcomes. We investigated whether quantifying TTV in nasopharyngeal samples upon emergency department (ED) admission could serve as an early predictor of COVID-19 severity. Retrospective single-center study in the ED of Saint-Louis Hospital in Paris, France. TTV DNA was quantified in nasopharyngeal swab samples collected for SARS-CoV-2 testing. Among 295 SARS-CoV-2 infected patients, 92 returned home, 160 were admitted to medical wards, and 43 to the intensive care unit (ICU). Elevated TTV loads were observed in ICU patients (median: 3.02 log copies/mL, interquartile range [IQR]: 2.215-3.825), exceeding those in discharged (2.215, [0; 2.962]) or hospitalized patients (2.24, [0; 3.29]) (p = 0.006). Multivariate analysis identified diabetes, obesity, hepatitis, fever, dyspnea, oxygen requirement, and TTV load as predictors of ICU admission. A 2.91 log10 copies/mL TTV threshold independently predicted ICU admission. Nasopharyngeal TTV quantification in SARS-CoV-2 infected patients is linked to the likelihood of ICU admission and might reflect respiratory immunosuppression.

A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP.

The anti-von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.