Publications by authors named "Elie Azoulay"

588 Publications

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

Lancet 2022 Jan 19. Epub 2022 Jan 19.

Hôtel Dieu University Hospital, Department of Anesthesia and Critical Care, Nantes, France.

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.
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http://dx.doi.org/10.1016/S0140-6736(21)02176-0DOI Listing
January 2022

Prevalence, Intensity and Clinical Impact of Dyspnea in Critically Ill Patients Receiving Invasive Ventilation.

Am J Respir Crit Care Med 2022 Jan 21. Epub 2022 Jan 21.

groupe hospitalier pitié-salpêtrière, Service de Pneumologie, PARIS, France.

Background: Dyspnea is a traumatic experience. Only limited information is available on dyspnea in intubated critically ill patients. Our objectives were 1) To quantify the prevalence and severity of dyspnea, 2) To evaluate the impact of dyspnea on intensive care unit (ICU) length of stay and post-traumatic stress disorder (PTSD) 90 days after ICU discharge.

Methods: Prospective cohort study in 10 ICUs in France. In patients intubated for more than 24 hours, dyspnea was quantified with a visual analog scale (from zero to 10) as soon as they were able to communicate, the following day and prior spontaneous breathing trials. PTSD was defined by an Impact of Event Scale-Revised score ≥ 22.

Results: Among the 612 patients assessed, 34% reported dyspnea, with a median dyspnea rating of 5 (interquartile range, 4-7). ICU length of stay was not significantly different between dyspneic and non-dyspneic patients (6 [3-12] and 6 [3-13] days, respectively; P=0.781). Mortality was not different between groups. Of the 153 patients interviewed on day 90, a higher proportion of individuals with probable PTSD was observed among patients who were dyspneic on enrolment (29% vs. 13%, P=0.017). The density of dyspnea (number of dyspneic episodes divided by time from enrolment to extubation) were independently associated with post-traumatic stress disorder (odds ratio: 1.07, 95% confidence interval: 1.01-1.13, P=0.031).

Conclusion: Dyspnea was frequent and intense in intubated critically ill patients. ICU length of stay was not significantly different among patients reporting dyspnea, but PTSD was more frequent at day 90.
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http://dx.doi.org/10.1164/rccm.202108-1857OCDOI Listing
January 2022

Undocumented migrants in French intensive care units in 2011-2018: retrospective nationwide study.

Intensive Care Med 2022 Jan 19. Epub 2022 Jan 19.

Service de Médecine Intensive et Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France.

Purpose: Whether undocumented migrants admitted to intensive care units (ICUs) have specific features is unknown. We aimed to determine the features and outcomes of undocumented migrants admitted to French ICUs.

Methods: We retrospectively included all undocumented adult migrants admitted in 2011-2018 and compared them to the general ICU population. We also compared these two groups matched on age, sex, severity, comorbidities, reason for ICU admission and public/private hospital.

Results: We identified 14,554 ICU stays, with an increase from 2 to 4‰ of all ICU admissions over time. Shock (16.7%), post-operative care (13.8%), and trauma (10.5%) were the main reasons for ICU admission. Compared to general ICU patients, migrants were younger and had greater disease severity. After adjustment on age and sex, the following were more common in migrants: shock (OR 1.2 [1.14-1.25]; P < 0.0001), infections (1.48 [1.38-1.54]; P < 0.001), acute respiratory failure (1.09 [1.03-1.15]; P = 0.006), acute kidney injury (1.12 [1.05-1.19]; P < 0.001), obstetric events (1.53 [1.66-1.81]; P < 0.0001), and neurological deficits (1.19 [1.12-1.27]; P < 0.0001). In the matched study, migrants more often required vasopressors, mechanical ventilation, and renal replacement therapy; had longer ICU stays (median 4 [2-8] vs. 4 [2-7] days; P < 0.0001) and hospital stays (10 [5-20] vs. 8 [4-15]; P < 0.0001) and had higher hospital costs (14.2 ± 23.6 vs. 13.4 ± 11.5 K€; P < 0.0001). Hospital mortality was similar (6.7% vs. 6.6%; P = 0.69).

Conclusion: Admissions of undocumented migrants to French ICUs doubled from 2011 to 2018. The patients were younger and, although sicker, achieved similar outcomes to those in general ICU patients.
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http://dx.doi.org/10.1007/s00134-021-06606-9DOI Listing
January 2022

Combination of mycological criteria: a better surrogate to identify COVID-19 associated pulmonary aspergillosis patients and evaluate prognosis?

J Clin Microbiol 2022 Jan 5:JCM0216921. Epub 2022 Jan 5.

Institut Pasteur, Université de Paris, CNRS, Unité de Mycologie Moléculaire, UMR2000, F-75015 Paris, France.

Diagnosis of COVID-19 associated pulmonary aspergillosis remains unclear especially in non-immunocompromised patients. The aim of this study was to evaluate seven mycological criteria and their combination in a large homogenous cohort of patients. All successive patients (n=176) hospitalized for COVID-19 requiring mechanical ventilation and who clinically worsened despite appropriate standard of care were included over a one-year period. Direct examination, culture, qPCR (-qPCR) and galactomannan was performed on all respiratory samples (n=350). Serum galactomannan, ß-D-glucan and plasma -qPCR were also assessed. Criteria were analyzed alone or in combination in relation to mortality rate. Mortality was significantly different in patients with 0, ≤2 and ≥3 positive criteria (logrank test, p=0.04) with death rate of 43.1, 58.1 and 76.4% respectively. Direct examination, plasma qPCR and serum galactomannan were associated with a 100% mortality rate. Bronchoalveolar lavage (BAL) galactomannan and positive respiratory sample culture were often found as isolated markers (28.1 and 34.1%) and poorly repeatable when a second sample was obtained. DNA was detected in 13.1% of samples (46/350) with significantly lower Cq when associated with at least one other criteria (30.2 35.8) (p<0.001). Combination of markers and/or blood biomarkers and/or direct respiratory sample examination seems more likely to identify patients with CAPA. -qPCR may help identifying false positive results of BAL galactomannan testing and culture on respiratory samples while quantifying fungal burden accurately.
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http://dx.doi.org/10.1128/JCM.02169-21DOI Listing
January 2022

We are proud of you Jamie.

Intensive Care Med 2022 Jan 3. Epub 2022 Jan 3.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.

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http://dx.doi.org/10.1007/s00134-021-06566-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720557PMC
January 2022

Critically ill patients with severe infections related to Geotrichum species: A French retrospective multicentre study.

Mycoses 2022 Feb 8;65(2):226-232. Epub 2021 Dec 8.

AP-HP, Hôpital Saint-Louis, Medical ICU, Université de Paris, Paris, France.

Objectives: Geotrichum spp can be responsible for severe infections in immunocompromised patients. We aim to describe Geotrichum-related infections in the ICU and to assess risk factors of mortality.

Methods: Retrospective multicentre study, conducted in 14 French ICUs between 2002 and 2018, including critically ill adult patients with proven or probable infection related to Geotrichum species. Data were obtained from the medical charts.

Results: Thirty-six patients, median age 60 years IQR [53; 66] were included. Most of the patients had haematological malignancies (78%). The reason for ICU admission was shock in half of the patients (n = 19, 53%) and respiratory failure in thirteen patients (36%). Median SOFA score was 8.5 IQR [7; 15]. Time between ICU admission and fungal diagnosis was 2.5 days [-1; 4]. Infection was disseminated in 27 (75%) patients with positive blood cultures in 25 patients (69%). Thirty patients (83%) received curative antifungal treatment in the ICU, in a median time of 1 day [0;1] after ICU admission. Twenty-four patients (67%) died in the ICU and hospital mortality rate was 69%. The number and extent of organ failures, as represented by SOFA score, were associated with mortality.

Conclusions: This study demonstrates poor outcome in critically ill patients with Geotrichum-related infections, which encourages a high level of suspicion.
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http://dx.doi.org/10.1111/myc.13407DOI Listing
February 2022

Randomised clinical trials in critical care: past, present and future.

Intensive Care Med 2021 Dec 2. Epub 2021 Dec 2.

Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Randomised clinical trials (RCTs) are the gold standard for providing unbiased evidence of intervention effects. Here, we provide an overview of the history of RCTs and discuss the major challenges and limitations of current critical care RCTs, including overly optimistic effect sizes; unnuanced conclusions based on dichotomization of results; limited focus on patient-centred outcomes other than mortality; lack of flexibility and ability to adapt, increasing the risk of inconclusive results and limiting knowledge gains before trial completion; and inefficiency due to lack of re-use of trial infrastructure. We discuss recent developments in critical care RCTs and novel methods that may provide solutions to some of these challenges, including a research programme approach (consecutive, complementary studies of multiple types rather than individual, independent studies), and novel design and analysis methods. These include standardization of trial protocols; alternative outcome choices and use of core outcome sets; increased acceptance of uncertainty, probabilistic interpretations and use of Bayesian statistics; novel approaches to assessing heterogeneity of treatment effects; adaptation and platform trials; and increased integration between clinical trials and clinical practice. We outline the advantages and discuss the potential methodological and practical disadvantages with these approaches. With this review, we aim to inform clinicians and researchers about conventional and novel RCTs, including the rationale for choosing one or the other methodological approach based on a thorough discussion of pros and cons. Importantly, the most central feature remains the randomisation, which provides unparalleled restriction of confounding compared to non-randomised designs by reducing confounding to chance.
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http://dx.doi.org/10.1007/s00134-021-06587-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636283PMC
December 2021

A multivariate model for successful publication of intensive care medicine randomized controlled trials in the highest impact factor journals: the SCOTI score.

Ann Intensive Care 2021 Nov 27;11(1):165. Epub 2021 Nov 27.

Department of Anesthesia and Intensive Care Unit, Regional University Hospital of Montpellier, St-Eloi Hospital, University of Montpellier, PhyMedExp, INSERM U1046, CNRS UMR, 9214 CEDEX 5, Montpellier, France.

Background: Critical care randomized controlled trials (RCTs) are often published in high-impact journals, whether general journals [the New England Journal of Medicine (NEJM), The Lancet, the Journal of the American Medical Association (JAMA)] or critical care journals [Intensive Care Medicine (ICM), the American Journal of Respiratory and Critical Care Medicine (AJRCCM), Critical Care Medicine (CCM)]. As rejection occurs in up to 97% of cases, it might be appropriate to assess pre-submission probability of being published. The objective of this study was to develop and internally validate a simplified score predicting whether an ongoing trial stands a chance of being published in high-impact general journals.

Methods: A cohort of critical care RCTs published between 1999 and 2018 in the three highest impact medical journals (NEJM, The Lancet, JAMA) or the three highest impact critical care journals (ICM, AJRCCM, CCM) was split into two samples (derivation cohort, validation cohort) to develop and internally validate the simplified score. Primary outcome was journal of publication assessed as high-impact general journal (NEJM, The Lancet, JAMA) or critical care journal (ICM, AJRCCM, CCM).

Results: A total of 968 critical care RCTs were included in the predictive cohort and split into a derivation cohort (n = 510) and a validation cohort (n = 458). In the derivation cohort, the sample size (P value < 0.001), the number of centers involved (P value = 0.01), mortality as primary outcome (P value = 0.002) or a composite item including mortality as primary outcome (P value = 0.004), and topic [ventilation (P value < 0.001) or miscellaneous (P value < 0.001)] were independent factors predictive of publication in high-impact general journals, compared to high-impact critical care journals. The SCOTI score (Sample size, Centers, Outcome, Topic, and International score) was developed with an area under the ROC curve of 0.84 (95% Confidence Interval, 0.80-0.88) in validation by split sample.

Conclusions: The SCOTI score, developed and validated by split sample, accurately predicts the chances of a critical care RCT being published in high-impact general journals, compared to high-impact critical care journals.
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http://dx.doi.org/10.1186/s13613-021-00954-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626742PMC
November 2021

Coronavirus disease 2019 in immunocompromised patients: a comprehensive review of coronavirus disease 2019 in hematopoietic stem cell recipients.

Curr Opin Crit Care 2022 02;28(1):83-89

Medical Intensive Care Unit, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris (APHP), University de Paris, Paris, France.

Purpose Of Review: Immunocompromised patients are notably vulnerable to severe coronavirus disease 2019. This review summarizes COVID-19 features and outcomes in autologous and allogeneic hematopoietic stem cell transplantation (HSCT) recipients.

Recent Findings: Recent findings suggest that HSCT recipients exhibit a high burden of comorbidities and COVID-19 clinical features almost similar to the general COVID population. Furthermore, HSCT recipients exhibit a protracted SARS-CoV-2 shedding, prolonging duration of symptoms and promoting the generation of highly mutated viruses. Last, most of studies report a higher COVID-19 mortality in HSCT recipients, mainly driven by age, comorbidities, time from transplantation, and immunosuppression because of both treatments and underlying hematological malignancy.

Summary: Further studies are warranted to determine the proper impact of HSCT-related immune disorders on COVID-19 outcomes, and to evaluate specific treatments and vaccination strategy in this high-risk population. Taken together, those findings emphasize the need for more rigorous surveillance and preemptive measures for all HSCT recipients.
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http://dx.doi.org/10.1097/MCC.0000000000000907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8711307PMC
February 2022

Infection control in the intensive care unit: expert consensus statements for SARS-CoV-2 using a Delphi method.

Lancet Infect Dis 2021 Nov 10. Epub 2021 Nov 10.

IRCCS for Oncology and Neurosciences, San Martino Policlinico Hospital, Genoa, Italy; University of Genoa, Genoa, Italy.

During the current COVID-19 pandemic, health-care workers and uninfected patients in intensive care units (ICUs) are at risk of being infected with SARS-CoV-2 as a result of transmission from infected patients and health-care workers. In the absence of high-quality evidence on the transmission of SARS-CoV-2, clinical practice of infection control and prevention in ICUs varies widely. Using a Delphi process, international experts in intensive care, infectious diseases, and infection control developed consensus statements on infection control for SARS-CoV-2 in an ICU. Consensus was achieved for 31 (94%) of 33 statements, from which 25 clinical practice statements were issued. These statements include guidance on ICU design and engineering, health-care worker safety, visiting policy, personal protective equipment, patients and procedures, disinfection, and sterilisation. Consensus was not reached on optimal return to work criteria for health-care workers who were infected with SARS-CoV-2 or the acceptable disinfection strategy for heat-sensitive instruments used for airway management of patients with SARS-CoV-2 infection. Well designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.
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http://dx.doi.org/10.1016/S1473-3099(21)00626-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580499PMC
November 2021

A Research Agenda for Precision Medicine in Sepsis and Acute Respiratory Distress Syndrome: An Official American Thoracic Society Research Statement.

Am J Respir Crit Care Med 2021 10;204(8):891-901

Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. The recent success of precision medicine in non-critical care settings has resulted from the confluence of large clinical and biospecimen repositories, innovative bioinformatics, and novel trial designs. Similar advances for precision medicine in sepsis and in the acute respiratory distress syndrome (ARDS) are possible but will require further investigation and significant investment in infrastructure. This project was funded by the American Thoracic Society Board of Directors. A multidisciplinary and diverse working group reviewed the available literature, established a conceptual framework, and iteratively developed recommendations for the Precision Medicine Research Agenda for Sepsis and ARDS. The following six priority recommendations were developed by the working group: ) the creation of large richly phenotyped and harmonized knowledge networks of clinical, imaging, and multianalyte molecular data for sepsis and ARDS; ) the implementation of novel trial designs, including adaptive designs, and embedding trial procedures in the electronic health record; ) continued innovation in the data science and engineering methods required to identify heterogeneity of treatment effect; ) further development of the tools necessary for the real-time application of precision medicine approaches; ) work to ensure that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic, and demographic groups; and ) the securement and maintenance of adequate and sustainable funding for precision medicine efforts. Precision medicine approaches that incorporate variability in genomic, biologic, and environmental factors may provide a path forward for better individualizing the delivery of therapies and improving care for patients with sepsis and ARDS.
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http://dx.doi.org/10.1164/rccm.202108-1908STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534611PMC
October 2021

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

CA Cancer J Clin 2022 Jan 6;72(1):78-93. Epub 2021 Oct 6.

Intensive Care in Hematologic and Oncologic Patients (iCHOP), Cologne, Germany.

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.
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http://dx.doi.org/10.3322/caac.21702DOI Listing
January 2022

Preempting critical care services for patients with hematological malignancies.

Intensive Care Med 2021 Oct 14;47(10):1140-1143. Epub 2021 Sep 14.

Hematology Department of the Saint-Louis Hospital, University of Paris, Paris, France.

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http://dx.doi.org/10.1007/s00134-021-06521-zDOI Listing
October 2021

Gastrointestinal bleeding in critically ill immunocompromised patients.

Ann Intensive Care 2021 Aug 21;11(1):130. Epub 2021 Aug 21.

Intensive Care Unit, Saint-Louis Hospital, Assistance Publique Des Hôpitaux de Paris, Paris, France.

Background: Acute gastrointestinal bleeding (GIB) may be a severe condition in immunocompromised patients and may require intensive care unit (ICU) admission. We aimed to describe the clinical spectrum of critically ill immunocompromised patients with GIB and identify risk factors associated with mortality and severe GIB defined by hemorrhagic shock, hyperlactatemia and/or the transfusion of more than 5 red blood cells units. Finally, we compared this cohort with a control population of non-immunocompromised admitted in ICU for GIB.

Results: Retrospective study in 3 centers including immunocompromised patients with GIB admitted in ICU from January, 1st 2010 to December, 31rd 2019. Risk factors for mortality and severe GIB were assessed by logistic regression. Immunocompromised patients were matched with a control group of patients admitted in ICU with GIB. A total of 292 patients were analyzed in the study, including 141 immunocompromised patients (compared to a control group of 151 patients). Among immunocompromised patients, upper GIB was more frequent (73%) than lower GIB (27%). By multivariate analysis, severe GIB was associated with male gender (OR 4.48, CI95% 1.75-11.42, p = 0.00), upper GIB (OR 2.88, CI95% 1.11-7.46, p = 0.03) and digestive malignant infiltration (OR 5.85, CI95% 1.45-23.56, p = 0.01). Conversely, proton pump inhibitor treatment before hospitalization was significantly associated with decreased risk of severe GIB (OR 0.25, IC95% 0.10-0.65, p < 0.01). Fifty-four patients (38%) died within 90 days. By multivariate analysis, mortality was associated with hemorrhagic shock (OR 2.91, IC95% 1.33-6.38, p = 0 .01), upper GIB (OR 4.33, CI95% 1.50-12.47, p = 0.01), and long-term corticosteroid therapy before admission (OR 2.98, CI95% 1.32-6.71, p = 0.01). Albuminemia (per 5 g/l increase) was associated with lower mortality (OR 0.54, IC95% 0.35-0.84, p = 0.01). After matching with a control group of non-immunocompromised patients, severity of bleeding was increased in immunocompromised patients, but mortality was not different between the 2 groups.

Conclusion: Mortality is high in immunocompromised patients with GIB in ICU, especially in patients receiving long term corticosteroids. Mortality of GIB is not different from mortality of non-immunocompromised patients in ICU. The prophylactic administration of proton pump inhibitors should be considered in this population.
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http://dx.doi.org/10.1186/s13613-021-00913-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380218PMC
August 2021

Outcomes in 1096 patients with severe thrombotic thrombocytopenic purpura before the Caplacizumab era.

PLoS One 2021 12;16(8):e0256024. Epub 2021 Aug 12.

Intensive Care Department, University of Paris, Saint-Louis Hospital, Paris, France.

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a diagnostic and therapeutic emergency. Therapeutic plasma exchange (TPE) combined with immunosuppression has been the cornerstone of the initial management. To produce optimal benefits, emerging treatments must be used against a background of best standard of care. Clarifying current uncertainties is therefore crucial.

Methods: The objective of this study was to analyze a large high-quality database (Marketscan) of TTP patients managed between 2005 and 2014, in the pre-caplacizumab era, in order to assess the impact of time to first TPE and use of first-line rituximab on mortality, and whether mortality declines over time.

Results: Among the 1096 included patients (median age 46 [IQR 35-55], 70% female), 28.8% received TPE before day 2 in the ICU. Hospital mortality was 7.6% (83 deaths). Mortality was independently associated with older age (hazard ratio [HR], 1.024/year; 95% confidence interval [95%CI], [1.009-1.040]), diagnosis of sepsis (HR, 2.360; 95%CI [1.552-3.588]), and the need for mechanical ventilation (HR, 4.103; 95%CI, [2.749-6.126]). Factors independently associated with lower mortality were TPE at ICU admission (HR, 0.284; 95%CI, [0.112-0.717]), TPE within one day after ICU admission (HR, 0.449; 95%CI, [0.275-0.907]), and early rituximab therapy (HR, 0.229; 95% CI, [0.111-0.471]). Delayed TPE was associated with significantly higher costs.

Conclusions: Immediate TPE and early rituximab are associated with improved survival in TTP patients. Improved treatments have led to a decline in mortality over time, and alternate outcome variables such as the use of hospital resources or longer term outcomes therefore need to be considered.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256024PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360509PMC
December 2021

Clinical and biological clusters of sepsis patients using hierarchical clustering.

PLoS One 2021 4;16(8):e0252793. Epub 2021 Aug 4.

UMR 1137 IAME INSERM- Paris Diderot University, Paris, France.

Background: Heterogeneity in sepsis expression is multidimensional, including highly disparate data such as the underlying disorders, infection source, causative micro-organismsand organ failures. The aim of the study is to identify clusters of patients based on clinical and biological characteristic available at patients' admission.

Methods: All patients included in a national prospective multicenter ICU cohort OUTCOMEREA and admitted for sepsis or septic shock (Sepsis 3.0 definition) were retrospectively analyzed. A hierarchical clustering was performed in a training set of patients to build clusters based on a comprehensive set of clinical and biological characteristics available at ICU admission. Clusters were described, and the 28-day, 90-day, and one-year mortality were compared with log-rank rates. Risks of mortality were also compared after adjustment on SOFA score and year of ICU admission.

Results: Of the 6,046 patients with sepsis in the cohort, 4,050 (67%) were randomly allocated to the training set. Six distinct clusters were identified: young patients without any comorbidities, admitted in ICU for community-acquired pneumonia (n = 1,603 (40%)); young patients without any comorbidities, admitted in ICU for meningitis or encephalitis (n = 149 (4%)); elderly patients with COPD, admitted in ICU for bronchial infection with few organ failures (n = 243 (6%)); elderly patients, with several comorbidities and organ failures (n = 1,094 (27%)); patients admitted after surgery, with a nosocomial infection (n = 623 (15%)); young patients with immunosuppressive conditions (e.g., AIDS, chronic steroid therapy or hematological malignancy) (n = 338 (8%)). Clusters differed significantly in early or late mortality (p < .001), even after adjustment on severity of organ dysfunctions (SOFA) and year of ICU admission.

Conclusions: Clinical and biological features commonly available at ICU admission of patients with sepsis or septic shock enabled to set up six clusters of patients, with very distinct outcomes. Considering these clusters may improve the care management and the homogeneity of patients in future studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252793PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336799PMC
November 2021

Coagulation disorders in patients with severe hemophagocytic lymphohistiocytosis.

PLoS One 2021 3;16(8):e0251216. Epub 2021 Aug 3.

AP-HP, Medical ICU, Hôpital Saint-Louis, Paris, France.

Background: Coagulation disorders are common in patients with hemophagocytic lymphohistiocytosis (HLH), associated with an increased risk of bleeding and death. We aim to investigate coagulation disorders and their outcome implications in critically ill patients with HLH.

Methods: We prospectively evaluated 47 critically ill patients with HLH (median age of 54 years [42-67]) between April 2015 and December 2018. Coagulation assessments were performed at day 1. Abnormal standard coagulation was defined as prothrombin time (PT) <50% and/or fibrinogen <2g/L. HLH aetiology was mostly ascribed to haematological malignancies (74% of patients).

Results: Coagulation disorders and severe bleeding events were frequent, occurring in 30 (64%) and 11 (23%) patients respectively. At day 1, median fibrinogen level was 2∙65g/L [1.61-5.66]. Fibrinolytic activity was high as suggested by increased median levels of D-dimers, fibrin monomers, PAI-1 (plasminogen activator inhibitor) and tPA (tissue plasminogen activator). Forty-one (91%) patients had a decreased ADAMTS13 activity (A Disintegrin-like And Metalloproteinase with ThromboSpondin type 1 repeats, member 13). By multivariable analysis, the occurrence of a severe bleeding (OR 3.215 [1.194-8.653], p = 0∙021) and SOFA score (Sepsis-Related Organ Failure Assessment) at day 1 (OR 1.305 per point [1.146-1.485], p<0∙001) were independently associated with hospital mortality. No early biological marker was associated with severe bleeding.

Conclusions: Hyperfibrinolysis may be the primary mechanism responsible for hypofibrinogenemia and may also participate in ADAMTS13 degradation. Targeting the plasmin system appears as a promising approach in severe HLH-related coagulation disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251216PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330932PMC
November 2021

Outcomes of ICU patients with and without perceptions of excessive care: a comparison between cancer and non-cancer patients.

Ann Intensive Care 2021 Jul 31;11(1):120. Epub 2021 Jul 31.

Hôpital Saint-Louis and University, Paris, France.

Background: Whether Intensive Care Unit (ICU) clinicians display unconscious bias towards cancer patients is unknown. The aim of this study was to compare the outcomes of critically ill patients with and without perceptions of excessive care (PECs) by ICU clinicians in patients with and without cancer.

Methods: This study is a sub-analysis of the large multicentre DISPROPRICUS study. Clinicians of 56 ICUs in Europe and the United States completed a daily questionnaire about the appropriateness of care during a 28-day period. We compared the cumulative incidence of patients with concordant PECs, treatment limitation decisions (TLDs) and death between patients with uncontrolled and controlled cancer, and patients without cancer.

Results: Of the 1641 patients, 117 (7.1%) had uncontrolled cancer and 270 (16.4%) had controlled cancer. The cumulative incidence of concordant PECs in patients with uncontrolled and controlled cancer versus patients without cancer was 20.5%, 8.1%, and 9.1% (p < 0.001 and p = 0.62, respectively). In patients with concordant PECs, we found no evidence for a difference in time from admission until death (HR 1.02, 95% CI 0.60-1.72 and HR 0.87, 95% CI 0.49-1.54) and TLDs (HR 0.81, 95% CI 0.33-1.99 and HR 0.70, 95% CI 0.27-1.81) across subgroups. In patients without concordant PECs, we found differences between the time from admission until death (HR 2.23, 95% CI 1.58-3.15 and 1.66, 95% CI 1.28-2.15), without a corresponding increase in time until TLDs (NA, p = 0.3 and 0.7) across subgroups.

Conclusions: The absence of a difference in time from admission until TLDs and death in patients with concordant PECs makes bias by ICU clinicians towards cancer patients unlikely. However, the differences between the time from admission until death, without a corresponding increase in time until TLDs, suggest prognostic unawareness, uncertainty or optimism in ICU clinicians who did not provide PECs, more specifically in patients with uncontrolled cancer. This study highlights the need to improve intra- and interdisciplinary ethical reflection and subsequent decision-making at the ICU.
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http://dx.doi.org/10.1186/s13613-021-00895-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325749PMC
July 2021

Imbalance of von Willebrand factor and ADAMTS13 axis is rather a biomarker of strong inflammation and endothelial damage than a cause of thrombotic process in critically ill COVID-19 patients.

J Thromb Haemost 2021 09 27;19(9):2193-2198. Epub 2021 Jul 27.

Service d'Hématologie biologique, Hôpital Lariboisière, AP-HP.Nord, Université de Paris, Paris, France.

Background: Critically ill patients with coronavirus disease 2019 (COVID-19) are prone to developing macrothrombosis and microthrombosis. COVID-19 has been reported to be rarely associated with thrombotic microangiopathies. A disintegrin and metalloprotease with thrombospondin type I repeats, member 13 (ADAMTS13) severe deficiency, the hallmark of thrombotic thrombocytopenic purpura (TTP), induces the formation of platelet, unusually large von Willebrand factor (VWF) multimer microthrombi. In immune-mediated TTP, ADAMTS13 adopts specifically an open conformation. The VWF/ADAMTS13 couple may contribute to the microthrombi formation in pulmonary alveolar capillaries in COVID-19.

Objective: To investigate clinical features, hemostatic laboratory parameters, VWF/ADAMTS13 axis, and ADAMTS13 conformation in critically ill COVID-19 patients at admission.

Methods: Fifty three critically ill COVID-19 patients were enrolled between March 18 and May 9 2020 in a monocentric hospital.

Results: The median age was 59 years and the male-to-female ratio was 2.8/1. We reported seven pulmonary embolisms and 15 deaths. Biological investigations showed increased fibrinogen and factor V levels, and strongly increased D-dimers correlated with mortality. No patient presented severe thrombocytopenia nor microangiopathic hemolytic anemia. An imbalance between high VWF antigen levels and normal or slightly decreased ADAMTS13 activity levels (strongly elevated VWF/ADAMTS13 ratio) was correlated with mortality. Three patients had a partial quantitative deficiency in ADAMTS13. We also reported a closed conformation of ADAMTS13 in all patients, reinforcing the specificity of an open conformation of ADAMTS13 as a hallmark of TTP.

Conclusion: We suggest that slightly decreased or normal ADAMTS13 activity and highly elevated VWF are rather biomarkers reflecting both the strong inflammation and the endothelial damage rather than drivers of the thrombotic process of COVID-19.
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http://dx.doi.org/10.1111/jth.15445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420340PMC
September 2021

Systemic autoimmune disorders associated with thrombotic microangiopathy: A cross-sectional analysis from the French National TMA registry: Systemic autoimmune disease-associated TMA.

Eur J Intern Med 2021 11 24;93:78-86. Epub 2021 Jun 24.

French Reference Centre for Thrombotic Microangiopathies, Saint-Antoine Hospital, Paris, France; Haematology Department, Saint-Antoine Hospital, Paris, France; Sorbonne University, Paris, France. Electronic address:

Context: The management of systemic auto-immune diseases (SAID) -associated thrombotic microangiopathies (TMA) [SAID-TMA] remains debated.

Objectives: To provide a demographic, clinical and therapeutic picture of SAID-TMA.

Methods: A cross-sectional analysis was conducted on adult patients presenting with SAID and TMA from the French National TMA Registry over a 20-year period. Clinical features were extracted and compared to those from a historical cohort of atypical haemolytic and uremic syndrome (aHUS) patients.

Results: Forty-one patients with SAID-TMA were compared to 78 patients with aHUS from a historical cohort. Connective tissue diseases (CTD) were systemic lupus erythematosus (n=18), primary Sjögren's syndrome (n=7), systemic sclerosis (n=11), mixed CTD (n=2) and 2 cases of vasculitides, including 7 overlapping forms and 8 cases of primary antiphospholipid syndromes (APLS). Patients with SAID-TMA generally had pre-existing chronic kidney failure (OR= 3.17, 95%CI: 1.204 to 7.923; p= 0.016) compared to aHUS patients, though creatinine levels were significantly lower (216 [IQR, 108-334] µmol/L vs. 368 [IQR, 170-722] µmol/L; p= 0.002). Patients were less likely to recover if renal replacement therapy was needed at onset (OR= 0.07; 0.02 to 0.34; p <0.0005). Two patients died. Thirty patients responded to immunosuppressive treatment and complete remission was achieved in 25 cases. By contrast, therapeutic plasma exchange (TPE) did not have an early effect on TMA features at Day-7 nor Day-15 (p >0.05).

Conclusion: The management of SAID-TMA implies an early initiation of immunosuppressive drugs for flares of the associated SAID, whereas TPE seem ineffective. KEY MESSAGES.
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http://dx.doi.org/10.1016/j.ejim.2021.05.040DOI Listing
November 2021

Pattern of Brain Injury in Patients With Thrombotic Thrombocytopenic Purpura in the Precaplacizumab Era.

Crit Care Med 2021 10;49(10):e931-e940

Service de Médecine Intensive-Réanimation, Hôpital Saint-Louis, APHP, Paris, France.

Objectives: To describe short- and long-term neurologic prognosis of patients with thrombotic thrombocytopenic purpura and to identify clusters associated with evolution.

Design: Prospective French cohort.

Setting: ICU in a reference center.

Patients: All consecutive patients with newly diagnosed thrombocytopenic purpura.

Intervention: Comprehensive clinical, biological, and radiological evaluation at admission. Neurocognitive recovery was assessed using Glasgow Outcome Scale (range 1-5, with 1 representing death and 5 representing no or minimal neurologic deficit).

Measurements And Main Results: Among the 130 newly diagnosed patients with thrombocytopenic purpura, 108 (83%; age 43 [30-52]; 73% women) presented with neurologic signs, including headaches (51%), limb weakness, paresthesia, and/or aphasia (49%), pyramidal syndrome (30%), decreased consciousness (20%), seizure (19%), cognitive impairment (34%), cerebellar syndrome (18%), and visual symptoms (20%). A hierarchical cluster analysis identified three distinct groups of patients. Cluster 1 included younger patients (37 [27-48], 41 [32-52], and 48 [35-54], in clusters 1, 2 and 3, respectively; p = 0.045), with a predominance of headaches (75%, 27%, and 36%; p < 0.0001). Cluster 2 patients had ataxic gait and cerebellar syndrome (77%, 0%, and 0%; p < 0.0001) and dizziness (50%, 0%, and 0%; p < 0.0001). Cluster 3 included patients with delirium (36%, 0%, and 9%; p < 0.0001), obtundation (58%, 0%, and 24%; p < 0.0001), and seizure (36%, 0%, and 14%; p < 0.0001). Acute kidney injury was 32%, 68%, and 77%, in clusters 1, 2, and 3, respectively (p < 0.0001). The three clusters did not differ for other biological or brain imaging. After a median follow-up of 34 months (12-71 mo), 100 patients (93%) were alive with full neurocognitive recovery (i.e., Glasgow Outcome Scale score 5) in 89 patients (89%). Patients from cluster 1 more frequently exhibited full recovery (Glasgow Outcome Scale score of 5) compared with clusters 2 and 3, (44 [98%], 13 [65%], and 21 [60%] at 3 mo; p < 0.0001), (44 [100%], 15 [68%], and 23 [69%] at 6 mo; p < 0.0001), and (40 [100%], 15 [79%], and 20 [57%] at 1 yr; p < 0.0001).

Conclusions: Initial clinical neurologic evaluation in thrombocytopenic purpura patients distinguishes three groups of patients with different clinical and functional outcomes.
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http://dx.doi.org/10.1097/CCM.0000000000005164DOI Listing
October 2021

Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis.

Intensive Care Med 2021 08 23;47(8):819-834. Epub 2021 Jun 23.

Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St. James's Hospital, Dublin, Ireland.

Purpose: Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance.

Methods: A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology.

Results: The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients' clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients.

Conclusion: CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study.
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http://dx.doi.org/10.1007/s00134-021-06449-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220883PMC
August 2021

An Interprofessional Process for the Limitation of Life-Sustaining Treatments at the End of Life in France.

J Pain Symptom Manage 2022 Jan 19;63(1):160-170. Epub 2021 Jun 19.

Philip R. Lee Institute of Health Policy Studies (D.D., T.M., E.D.), University of California, San Francisco, California, USA; Division of Hospital Medicine (E.D.), Department of Medicine, University of California, San Francisco, California, USA. Electronic address:

Context: The provision of potentially non-beneficial life-sustaining treatments (LSTs) remains a challenging problem. In 2005, legislation in France established an interprofessional process by which non-beneficial LSTs could be withheld or withdrawn, permitting exploration of the effects of such a legally-protected process and its implementation.

Objectives: To characterize intensive care unit (ICU) interprofessional team decision-making and consensus-building practices regarding withholding and withdrawing of LSTs in two Parisian hospitals and to explore physician and nurse perceptions of and experiences with these practices.

Methods: This was an exploratory qualitative study utilizing thematic analysis of semi-structured, in-depth interviews of physicians and nurses purposively sampled based on level of training and experience from two hospitals in Paris, France.

Results: A total of 25 participants were interviewed. Participants reported that the two Parisian hospitals in this study have each created an interprofessional process for withholding or withdrawing non-beneficial LSTs, providing insight into how norms of decision-making respond to systems-level legal changes. Participants reported that these processes tended to be consistent across several domains: maintaining unified messaging with patients, empowering nurses to participate in end-of-life decision-making, reducing moral distress provoked by end-of-life decisions, and shaping the ethical milieu within which end-of-life decision-making takes place.

Conclusions: The architecture of the interprofessional process created at two Parisian hospitals and its perceived benefits may be useful to clinicians and policy-makers attempting to establish processes, policies, or legislation directed at withholding or withdrawing potentially non-beneficial LSTs in the United States and elsewhere.
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http://dx.doi.org/10.1016/j.jpainsymman.2021.06.016DOI Listing
January 2022

Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009-2017.

Emerg Infect Dis 2021 ;27(7):1876-1885

We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC) in 96 adults enrolled in the cohort of the National Reference Center for Thrombotic Microangiopathies network in France during 2009-2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.
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http://dx.doi.org/10.3201/eid2707.204638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237898PMC
July 2021

Lived Experiences of Family Members of Patients With Severe COVID-19 Who Died in Intensive Care Units in France.

JAMA Netw Open 2021 06 1;4(6):e2113355. Epub 2021 Jun 1.

Famiréa Research Group, Medical Intensive Care Unit, Assistance Publique-Hȏpitaux de Paris, Saint Louis University Hospital, Paris, France.

Importance: During the initial surge of the COVID-19 pandemic, family members were often separated from their loved ones admitted to intensive care units (ICUs), with a potential for negative experiences and psychological burden.

Objective: To better understand the experiences of bereaved family members of patients who died in an ICU during the COVID-19 pandemic, from the time of hospital admission until after the patient's death.

Design, Setting, And Participants: This qualitative study used semistructured, in-depth interviews to collect experiences from bereaved family members of patients who died from severe COVID-19 in 12 ICUs during the first wave of the pandemic in France. Purposeful sampling was used to ensure the diversity of study participants with respect to sex, age, relationship with the patient, and geographic location. All data were collected between June and September 2020, and data analysis was performed from August to November 2020.

Main Outcomes And Measures: Interviews were conducted 3 to 4 months after the patient's death and were audio-recorded and analyzed using thematic analysis.

Results: Among 19 family members interviewed (median [range] age, 46 [23-75] years; 14 [74%] women), 3 major themes emerged from qualitative analysis. The first was the difficulty in building a relationship with the ICU clinicians and dealing with the experience of solitude: family members experienced difficulties in establishing rapport and bonding with the ICU team as well as understanding the medical information. Distance communication was not sufficient, and participants felt it increased the feeling of solitude. The second involved the patient in the ICU and the risks of separation: because of restricted access to the ICU, family members experienced discontinuity and interruptions in the relationship with their loved one, which were associated with feelings of powerlessness, abandonment, and unreality. The third was regarding disruptions in end-of-life rituals: family members described "stolen moments" after the patient's death, generating strong feelings of disbelief that may lead to complicated grief.

Conclusions And Relevance: This qualitative study found that during the initial wave of the COVID-19 pandemic in France, bereaved family members described a disturbed experience, both during the ICU stay and after the patient's death. Specific family-centered crisis guidelines are needed to improve experiences for patients, families, and clinicians experiences.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.13355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218069PMC
June 2021

Reply to Sklar and Yarnell and to Stahl

Am J Respir Crit Care Med 2021 09;204(6):739

Saint-Louis Hospital and Sorbonne University Paris, France.

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http://dx.doi.org/10.1164/rccm.202104-1072LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521695PMC
September 2021
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