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Background: Cerebral aspergillosis (CA) is a life-threatening disease for which diagnosis and management remain challenging. Detailed analyses from large cohorts are lacking.Methods: We included 119 cases of proven (n = 54) or probable (n = 65) CA diagnosed between 2006 and 2018 at 20 French hospitals. Data were collected at baseline and during follow-up. Cerebral imaging was reviewed centrally by two neuroradiologists.Results: The most frequent underlying conditions were hematological malignancy (40%) and solid organ transplantation (29%). Galactomannan was detected in the serum of 64% of patients. In 75% of cases, at least one of galactomannan, Aspergillus PCR, and β-d-glucan was positive in the cerebrospinal fluid. Six-week mortality was 45%. Two distinct patterns of disease were identified according to presumed route of dissemination. Presumed haematogenous dissemination (n = 88) was associated with a higher frequency of impaired consciousness (64%), shorter time to diagnosis, the presence of multiple abscesses (70%), microangiopathy (52%), detection of serum galactomannan (69%) and Aspergillus PCR (68%), and higher six-week mortality (54%). By contrast, contiguous dissemination from the paranasal sinuses (n = 31) was associated with a higher frequency of cranial nerve palsy (65%), evidence of meningitis on cerebral imaging (83%), macrovascular lesions (61%), delayed diagnosis, and lower six-week mortality (30%). In multivariate analysis and in a risk prediction model, haematogenous dissemination, hematological malignancy and the detection of serum galactomannan were associated with higher six-week mortality.Conclusion: Distinguishing between hematogenous and contiguous dissemination patterns appears to be critical in the workup for CA, as they are associated with significant differences in clinical presentation and outcome. [ABSTRACT FROM AUTHOR]

Click here to view the Letter to the Editor by Pineton de Chambrun et al. [ABSTRACT FROM AUTHOR]

Dear Editor, Coronavirus disease 2019 (COVID-19) is associated with both severe systemic inflammation and a prothrombotic state, as reflected by significant increases in fibrinogen and D-dimers levels that have been associated with poor prognosis [1] and high rates of severe pulmonary embolism [2]. We herein describe the profile of aPLA positivity in a series of 25 critically ill patients with severe COVID-19 infection. Most patients had positive LA and double aPLA positivity which are associated with a high risk of venous and arterial thrombosis in antiphospholipid syndrome patients [4]. As we also recently noticed unexplained lengthening of activated partial thromboplastin time (aPTT) in some critically ill COVID-19 patients, we explored our patients for aPLA positivity. [Extracted from the article]

Introduction Despite recent improvement in cardiac arrest management, in-hospital cardiac arrest (IHCA) remains associated with poor outcome. Whereas its usefulness for out-of-hospital cardiac arrest seems poor, extracorporeal cardiopulmonary resuscitation (e-CPR; i.e. veno-arterial extracorporeal membrane oxygenation (VA-ECMO) under cardiopulmonary resuscitation) could be a life-saving strategy for refractory IHCA. Objective To describe the characteristics and outcomes of refractory IHCA patients supported by e-CPR in our institution. Method Retrospective cohort study of data prospectively collected. All patients implanted with a VA-ECMO for refractory IHCA from 2007 to 2017 were included. VA-ECMO was implanted at the cardiac arrest site by trained cardiac surgeons from our mobile circulatory assistance unit. After ECMO implantation, patients were all referred and managed in our ICU. A 1-yr follow-up phone call was given to each survivor. Results During the study period, 97 patients (mean age 50.9 ± 14.8 yrs) received e-CPR for refractory IHCA. 80.4% of IHCA had a cardiac origin. VA-ECMO was implanted in our ICU for 37% of them, in the cardiology department for 30%, in another hospital for 23%. Survival rate was 19.6% at hospital discharge, 15% at 1-yr follow-up, with a 1-yr CPC score of 1 [1–2]. Main causes of in-ICU deaths were multiple organ failure (71%) and post-anoxic encephalopathy (12%). Compared to 1-yr non-survivors, 1-yr survivors had similar no- and low-flow, their initial rhythm was more frequently shockable (69.2% versus 33.8%, respectively, P = 0.03) and their day-1 SOFA score was significantly lower (13 [10–14] versus 15 [12–17], respectively, P = 0.02). Conclusion e-CPR in refractory IHCA is associated with a 15% 1-yr survival rate. Survivors have a good 1-year CPC score. Next step is to determine prognosis factors to select the patients the most likely to benefit from this technique. [ABSTRACT FROM AUTHOR]

L'infection par le SARS-CoV-2 peut induire chez l'adulte un syndrome inflammatoire multisystémique (MIS-A). La myocardite fulminante est l'une des complications les plus graves du MIS-A. Des critères internationaux ont été établis par le Center for Disease Control and Prevention américain (US-CDC) pour faciliter son diagnostic. Cependant, certains patients présentant une myocardite fulminante dans un contexte de la COVID-19 ne répondent pas aux critères de l'US-CDC, suggérant l'existence de plusieurs phénotypes de myocardites fulminantes associées à la COVID-19. L'objectif de cette étude était de comparer les caractéristiques cliniques et l'évolution des myocardites fulminantes induites par la COVID-19 selon qu'elles répondent, ou non, aux critères du MIS-A établis par l'US-CDC. Etude rétrospective monocentrique incluant toutes les myocardites fulminantes induites par la COVID-19 admises dans un service de Médecine Intensive-Réanimation entre mars 2020 et juin 2021. Le critère de jugement principal était la mortalité intra-hospitalière. Pendant la durée de l'étude, 38 patients ont été admis en réanimation pour une myocardite fulminante (homme 66 %, âge moyen à l'admission ± DS 32 ± 15 ans) induite par la COVID-19. Les traitements des défaillances d'organes reçus par les patients étaient : dobutamine 79 %, noradrénaline 60 %, ventilation invasive 50 %, ECMO-VA 42 % et épuration extra-rénale 29 %. La mortalité intra-hospitalière était de 13 %. Vingt-cinq patients (66 %) répondaient aux critères du MIS-A (MIS-A +). Les patients MIS-A- présentaient : un délai plus court entre le début de la COVID-19 et la survenue de la myocardite ; une fraction d'éjection du ventricule gauche plus basse ; une plus grande fréquence des défaillance d'organes et avaient un risque plus important de recevoir une ECMO-VA (92 % vs. 16 %, p < 0,0001). La mortalité intra-hospitalière était plus élevée chez les MIS-A- (31 % vs. 4 %). Les MIS-A+ présentaient des taux circulants plus élevées d'IL-17, d'IL-22 et de TNFa alors que les MIS-A- présentaient des taux circulants plus important d'IFNa2 et d'IL-8. De plus, les anticorps anti-ARN polymérases III étaient présents chez 54 % des patients MIS-A- mais chez aucun patient MIS-A+. Les critères de MIS-A permettent d'identifier deux phénotypes au sein des myocardites fulminantes induites par la COVID-19. Les patients MIS-A+ et MIS-A- ont une présentation clinique, un pronostic et un profil immunologique très différents. Différencier ces deux entités semble important pour leurs traitements et pour mieux en comprendre la physiopathologie. [ABSTRACT FROM AUTHOR]

La myocardite fulminante associée aux auto-anticorps anti-ARN polymérases III (ARNpol3) est une entité récemment décrit associant la survenue de myocardites aiguës fulminantes et/ou de péricardites sévères, principalement d'origine grippale et volontiers récidivantes, chez des patients présentant des ARNpol3 sans sclérodermie systémique évidente. La gravité de cette maladie procède à la fois de la sévérité des épisodes de myocardites et du risque de récidive à chaque nouvelle infection virale. La physiopathologie de cette maladie est inconnue. L'objectif de cette étude était de poursuivre la description de cette entité pour mieux en connaître les contours et le pronostic. Nous avons conduit une étude rétrospective monocentrique entre janvier 2013 et janvier 2022 incluant les patients admis dans le service de Médecine Intensive-Réanimation ou de Médecine Interne d'un centre hospitalier universitaire tertiaire et présentant une myocardite fulminante et/ou une péricardite sévère en présence d'ARNpol3. Pendant la durée de l'étude, 25 patients (femme 80 %, âge moyen au premier épisode 35 ± 11,4) ont pu être inclus. Après un suivi de 39 [6–50] mois, 7 (28 %) patients étaient décédés, d'un premier épisode de myocardite (n = 2), d'une récidive fatale (n = 4) ou d'une autre cause (n = 1). Le nombre moyen d'épisodes par malade était de 1,6 ± 0,9 et le taux de récidive de 40 %. Tous les patients ont nécessité au moins une fois l'admission en soins critiques, pour une durée de 9 [5–14] jours en médiane. La fraction d'éjection ventriculaire minimale était de 5 [5–10] % et le zénith de troponine de 82 [19-370] fois la valeur supérieure de la normale. Un épanchement péricardique significatif était présent chez 94 % des patients, nécessitant un drainage dans 40 % des cas. Les marqueurs inflammatoires à l'admission étaient peu élevés : CRP 7 [5–14] mg/L, procalcitonine 0,1 [0,06–0,4] ng/mL et fibrinogène 3 [2,4–3,4] g/L. Les troubles de conduction et du rythme étaient rares : 3 et 7 % respectivement. Au cours de leurs séjours, les fréquences des traitements des défaillances d'organes étaient : dobutamine 83 %, ECMO-VA 77 %, amines vasopressives 70 %, ventilation mécanique 67 % et épuration extra-rénale 30 %. Deux patients ont été transplantés en raison d'une non récupération de la fonction ventriculaire gauche. En dehors de ces deux malades, tous les survivants ont récupéré une fonction cardiaque normale. Les causes des myocardites étaient : grippale 52 %, COVID-19 44 %, virus inconnu 12 %, autre virus 4 %. Quatre patients ont présenté une myocardite grippale et une myocardite de COVID-19. Les ARNpol3 étaient confirmés positifs à distance chez tous les malades (n = 17) après un délai médian de 8 [2,5–16,5] mois. Seuls deux patients avaient un score de classification de sclérodermie systémique ≥9 sans atteinte viscérale ou signe d'évolutivité. Un patient avait un antécédent de cancer en rémission complète. Deux patients ont reçu un traitement préventif des récidives par immunoglobulines intraveineuses. La myocardite associée aux ARNpol3 est une entité en cours d'exploration. Cette étude montre que la grippe et la COVID-19 sont les principales causes de myocardites. De plus, nombre important de nouveaux malades ont été diagnostiqués à l'occasion de la pandémie de COVID-19. La physiopathologie de cette maladie est inconnue et nécessite d'être étudiée. [ABSTRACT FROM AUTHOR]

Purpose: Fever is frequent after extracorporeal membrane oxygenation (ECMO) decannulation. We aimed to evaluate the incidence of post-decannulation fever and describe its causes., Methods: Adult ECMO patients who were successfully weaned from ECMO were retrospectively included. Minimal and maximal core temperatures were collected daily for each patient from 48 h before decannulation up to 5 days after. Patients were grouped according to the cause of fever (infection, thrombosis, or no evident cause) and compared. Plasma cytokine profile was obtained, each day from decannulation to 5 days after for 20 patients., Results: Between January 2021 and December 2022, 123 patients successfully weaned from ECMO were included. Post-decannulation fever occurred in 54 patients (44 %). It was associated with an infection in 39 patients (72 %) and with a thrombosis in 6 patients (11 %), and no cause was identified in the remaining 9 (17 %). Prolonged ECMO duration, extended ICU length-of-stay, diabetes and vascular comorbidities were significantly associated with a higher risk of infection. Finally, the pro-inflammatory cytokine profiles did not differ between febrile and afebrile patients., Conclusion: Post-decannulation fever was common, and was mainly due to infections or thrombosis. Fever should therefore not be considered as a benign inflammatory reaction until proven otherwise., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study examines the effects of levosimendan in patients refractory to dobutamine weaning., Methods: This retrospective study included patients with cardiogenic shock refractory to dobutamine weaning failure admitted between 2010 and 2022. Patients treated with another type of dobutamine alone were compared with those treated with levosimendan in combination with dobutamine. Successful inotrope withdrawal was defined as survival without catecholamine support, transplant, or definitive ventricular assist device at 30 days. Secondary outcomes included all-cause mortality at 30 and 90 days., Results: Among 349 patients with cardiogenic shock and failure to withdraw from dobutamine, levosimendan was administered in combination with dobutamine in 114 patients, and another type of dobutamine alone was administered in 235 patients. At 30 days, successful inotrope withdrawal occurred in 46 (43.4%) patients taking levosimendan plus dobutamine versus 24 (10.5%) patients in the dobutamine-only group (weighted odds ratio [OR] 4.99, 95% confidence interval [CI] 2.65-9.38; p < 0.001), with similar results at 90 days (weighted OR 6.16, 95% CI 3.22-11.78; p < 0.001). Levosimendan + dobutamine was associated with lower 30-day mortality (weighted OR 0.47, 95% CI 0.26-0.84; p = 0.01), with no difference at 90 days (weighted OR 0.67, 95% CI 0.39-1.14; p = 0.14)., Conclusion: Adding levosimendan to dobutamine may improve inotrope withdrawal success and reduce 30-day mortality in patients with initial weaning failure., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The ACTION-SHOCK registry offers a decade-long perspective on patients admitted with cardiogenic shock (CS)., Aims: To assess trends in the management and outcomes of patients with CS over 10 years., Methods: Trends in the characteristics, management and outcomes of patients with CS admitted into the cardiac intensive care unit of Pitié-Salpêtrière hospital from 2011 to 2020 were analysed. Short-term outcomes included in-hospital mortality, heart transplantation or ventricular assist device. Long-term outcomes were all-cause death or readmission for acute heart failure at 1 year., Results: Over a 10-year period, data from 700 patients with CS (median [interquartile range] age 61 [50-72] years; 73% of men) were analysed. The proportion of CS related to acute myocardial infarction decreased (from 45% in 2011-2012 to 27% in 2019-2020) while the proportions related to chronic coronary syndrome (18% to 23%) and non-ischaemic cardiomyopathies (37 to 51%) increased (P<0.01). The use of rescue extracorporeal membrane oxygenation remained stable (19 to 14%) and intra-aortic balloon pump use decreased (22% to 7%) (P<0.01). In-hospital mortality remained stable (27 to 29%) as did the proportions of patients discharged after transplantation (17 to 14%) or with a durable ventricular assist device (2 to 4%). Among patients discharged alive, death or readmission for acute heart failure at 1 year remained high (37 to 47%)., Conclusion: CS remained associated with a poor prognosis over the last decade. There are significant unmet needs in the management strategies of patients with CS., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: During a pandemic like COVID-19, hospital resources are constrained and accurate severity triage of the patients is required., Objective: The objective of this study is to estimate the predictive performances of candidate biomarkers for short-term worsening (STW) of COVID-19., Design: Prospective, multicenter (20 hospitals in Paris) cohort study of consecutive COVID-19 patients with systematic biobanking at admission, during the first waves of COVID-19 in France in 2020 (COVIDeF cohort)., Setting and Participants: Consecutive COVID-19 patients were screened for inclusion. They were excluded in presence of severity criteria defined by either an ICU admission, mechanical ventilation (including noninvasive ventilation), acute respiratory distress, or in-hospital death before sampling. Routine blood tests measured during usual care and centralized systematic measurement of creatine kinase, C-reactive protein (CRP), procalcitonin, soluble urokinase plasminogen activator receptor (suPAR), high-sensitive troponin T (TnT-hs), N terminal pro-B natriuretic peptide (NT-proBNP), calprotectin, platelet factor 4, mid-regional pro-adrenomedullin (MR-proADM), and proendothelin were performed., Outcome Measures and Analyses: The primary outcome was STW, defined by a severity criteria within 7 days. A backward stepwise logistic regression model and a 'best subset' approach were used to identify independent association, and the area under the receiving operator characteristics (AUROC) was computed., Results: Five hundred and eleven patients were analyzed, of whom 60 (11.7%) experienced STW. Median time to occurrence of a severity criteria was 3 days. At admission, lower values of eosinophils, lymphocytes, platelets, alanine aminotransferase, and higher values of neutrophils, creatinine, urea, CRP, TnT-hs, suPAR, NT-proBNP, calprotectin, procalcitonin, MR-proADM, and proendothelin were predictive of worsening. Stepwise logistic regression identified three biomarkers significantly associated with worsening: CRP [adjusted odds ratio (aOR): 1.10, 95% confidence interval (95% CI): 1.06-1.15 for a 10-unit increase, AUROC: 0.73 (0.66-0.79)], procalcitonin [aOR: 0.42, 95% CI: 0.22-0.81, AUROC: 0.69 (0.64-0.88)], and MR-proADM [aOR: 2.85, 95% CI: 1.74-4.69, AUROC: 0.75 (0.69-0.81)]. These biomarkers outperformed clinical variables except diabetes and cancer comorbidities., Conclusion: In this multicenter prospective study that assessed a large panel of biomarkers for COVID-19 patients, CRP, procalcitonin, and MR-proADM were independently associated with the risk of STW., Trial Registration: ClinicalTrials.gov NCT04352348., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The use of extracorporeal membrane oxygenation (ECMO) may alter blood levels of several drugs, including antibiotics, leading to under dosing of these drugs and thus to potential treatment failure. No data exist on pharmacokinetics of new antimicrobial, in particular ceftazidime/avibactam. We therefore perform this study to evaluate ceftazidime/avibactam blood levels in ECMO patients and find factors associated with underdosing., Methods: Retrospective observational study of patients on ECMO having received ceftazidime/avibactam and in whom trough blood levels of ceftazidime and avibactam were available. Main outcome measurement was the number of patients with ceftazidime and avibactam blood levels above predefined cut-off values, derived from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa, namely 8 mg/L for ceftazidime and 4 mg/L for avibactam, and explored factors associated with underdosing., Results: Twenty-three ceftazidime/avibactam trough levels were available in 14 ECMO patients, all of them having received veno-venous ECMO for SARS-CoV-2-associated pneumonia. Although ceftazidime levels were above 8 mg/L in all except one patient, nine (39%) of the avibactam dosages were below 4 mg/L. Increased renal clearance (creatinine clearance > 130 mL/min) was the main factor associated with under dosing, since 7 out of the 10 dosages below the predefined cut-offs were measured in patients with this condition., Conclusions: In ECMO patients receiving ceftazidime/avibactam, ceftazidime and avibactam serum levels are above EUCAST breakpoints in most cases, justifying the use of normal dosing in ECMO patients. Increased renal clearance may lead to ceftazidime and avibactam under dosing., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Posttraumatic stress disorder (PTSD) after a stay in the intensive care unit (ICU) can affect one in five ICU survivors. At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, admission to the ICU for COVID-19 was stressful due to the severity of this disease. This study assessed whether admission to the ICU for COVID-19 was associated with a higher prevalence of PTSD compared with other causes of ICU admission after adjustment for pre-ICU psychological factors., Methods: This prospective observational comparative cohort study included 31 ICUs. Eligible patients were adult ICU survivors hospitalized during the first wave of COVID-19 pandemic in France, regardless of the reason for admission. The prevalence of presumptive diagnosis of PTSD at 6 months was assessed using the PTSD Checklist for DSM-5 (PCL-5). Sociodemographics, clinical data, history of childhood trauma (Childhood Trauma Questionnaire [CTQ]), and exposure to potentially traumatic events (Life Events Checklist for DSM-5 [LEC-5]) were assessed., Results: Of the 778 ICU survivors included during the first wave of COVID-19 pandemic in France, 417 and 361 were assigned to the COVID-19 and non-COVID-19 cohorts, respectively. Fourteen (4.9%) and 11 (4.9%), respectively, presented with presumptive diagnosis of PTSD at 6 months (p = 0.976). After adjusting for age, sex, severity score at admission, use of invasive mechanical ventilation, ICU duration, CTQ and LEC-5, COVID-19 status was not associated with presumptive diagnosis of PTSD using the PCL-5. Only female sex was associated with presumptive diagnosis of PTSD. However, COVID-19 patients reported significantly more intrusion and avoidance symptoms than non-COVID patients (39% vs. 29%, p = 0.015 and 27% vs. 19%, p = 0.030), respectively. The median PCL-5 score was higher in the COVID-19 than non-COVID-19 cohort (9 [3, 20] vs. 4 [2, 16], p = 0.034)., Conclusion: Admission to the ICU for COVID-19 was not associated with a higher prevalence of PTSD compared with admission for another cause during the first wave of the COVID-19 pandemic in France. However, intrusion and avoidance symptoms were more frequent in COVID-19 patients than in non-COVID-19 patients., Trial Registration: Clinicaltrials.gov Identifier NCT03991611, registered on June 19, 2019., (© 2024. The Author(s).)

Purpose: The impact of VA-ECMO on early renal recovery (within 7 days after ECMO onset) in patients with pre-ECMO acute kidney injury and cardiogenic shock is unknown., Material and Methods: This retrospective single-center study included adult patients with cardiogenic shock rescued by VA-ECMO and severe AKI occurring before ECMO implantation (pre-ECMO AKI). Patients with early renal recovery (defined as at least a 50% decrease in peak serum creatinine or weaning from renal replacement therapy) were compared to patients without early renal recovery., Results: During 7 years, 145 patients with severe pre-ECMO AKI were included. Eighty-two patients had no early renal recovery whereas 63 had early renal recovery within 7 days after VA-ECMO onset. The median time to early renal recovery was 4 (3,6) days. Nephrotoxic antibiotics (HR = 0.35 [95% CI, 0.21-0.59], p < 0.001), median fluid balance during the first 7 days of VA-ECMO (HR = 0.77 [95% CI, 0.64-0.93], p = 0.008), pre-ECMO AKI stage 3 (HR = 0.36 [95% CI, 0.20-0.64], p < 0.001) and median vasoactive-inotropic score (HR = 0.99 [95% CI, 0.98,1.00], p = 0.035) were independently associated with no early renal recovery., Conclusions: Only 43% of patients with severe pre-ECMO AKI had early renal recovery after VA-ECMO initiation., Competing Interests: Declaration of Competing Interest Pr Combes reports grants from Getinge, and personal fees from Getinge, Baxter, and Xenios outside the submitted work. Pr Schmidt reports receiving personal fees from Getinge, Baxter, and Xenios, outside the submitted work. No other disclosures were reported., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Acute myocarditis is an inflammation of the myocardium that can cause life-threatening events. However, anti-inflammatory strategies did not reduce the risk of clinical outcomes in randomized trials. Recently, experimental studies have suggested that specific blockade of the interleukin-1β immune innate pathway could be effective in acute myocarditis., Aim: To test the hypothesis that inhibition of the interleukin-1β immune innate pathway can reduce the risk of clinical events in acute myocarditis., Methods: The "Anakinra versus placebo double blind Randomized controlled trial for the treatment of Acute MyocarditIS" (ARAMIS) trial (ClinicalTrials.gov identifier: NCT03018834) is a national multicentre randomized parallel-group double blind study among symptomatic patients with elevated cardiac troponin and cardiac magnetic resonance-proven acute myocarditis. Patients (n=120) are randomized within 72hours of hospital admission to receive a daily subcutaneous dose of anakinra 100mg or placebo during the hospitalization, in addition to standard of care, including an angiotensin-converting enzyme inhibitor and a beta-blocker. The primary endpoint is the number of days alive free from any myocarditis complication, including ventricular arrhythmias, heart failure, recurrent chest pain requiring medication and ventricular dysfunction (defined as left ventricular ejection fraction<50%), from randomization to 28 days after hospital discharge. At 28 days after discharge, patients with normal left ventricular ejection fraction are then randomized to angiotensin-converting enzyme inhibitor continuation or discontinuation and all patients are followed for 1 year, with regular left ventricular function evaluation., Conclusions: ARAMIS is the first trial evaluating inhibition of the interleukin-1β immune innate pathway in the setting of acute myocarditis. Although of small size, it will be the largest randomized trial in acute myocarditis, a serious and poorly studied cardiac condition., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation., Significance: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027., (©2023 American Association for Cancer Research.)

Introduction: Due to its bacteriological spectrum and efficacy in skin and soft tissue infections, ceftobiprole may be of interest for extracorporeal membrane oxygenation (ECMO) cannula-related infection. It is unknown whether ceftobiprole pharmacokinetics (PK) are changed by ECMO., Methods: A retrospective monocentric cohort study was performed of 35 patients with suspected ECMO-related cannula infections (28 on ECMO, seven after ECMO removal), who received ceftobiprole as empiric treatment and had ceftobiprole blood levels measured at trough, peak and CT50 (50% of the dosing interval). Ceftobiprole blood levels of the 28 patients on ECMO were compared with those of the seven patients without ECMO. Factors associated with low ceftobiprole trough levels were also explored., Results: Among the 35 patients included, 29 had a confirmed cannula-related infection and 48 pathogens were isolated. Ceftobiprole MIC was determined in 29 of these 48, and 23 (79%) were susceptible to ceftobiprole. Ceftobiprole blood levels (at trough, peak and CT50) were similar in ECMO and non-ECMO patients. Moreover, in patients whose pathogens responsible for infection were susceptible to ceftobiprole, 94% had a ceftobiprole trough level above the MIC. Ceftobiprole blood levels were decreased in patients with acute renal failure requiring renal replacement therapy (RRT) and in those with increased renal clearance (defined as creatinine clearance > 130 mL/min), independent of ECMO. No other factor was associated with modification of ceftobiprole PK/pharmacodynamics (PK/PD)., Conclusions: The ceftobiprole PK/PD was no different in patients during ECMO or after its withdrawal. Factors associated with decreased ceftobiprole blood levels were patients requiring RRT and those with increased renal clearance., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: Patients with type 2-diabetes mellitus (T2D), are characterized by visceral and ectopic adipose tissue expansion, leading to systemic chronic low-grade inflammation. As visceral adiposity is associated with severe COVID-19 irrespective of obesity, we aimed to evaluate and compare the predictive value for early intensive care or death of three fat depots (cardiac, visceral and subcutaneous) using computed tomography (CT) at admission for COVID-19 in consecutive patients with and without T2D., Methods: Two hundred and two patients admitted for COVID-19 were retrospectively included between February and June 2020 and distributed in two groups: T2D or non-diabetic controls. Chest CT with cardiac (CATi), visceral (VATi) and subcutaneous adipose tissue (SATi) volume measurements were performed at admission. The primary endpoint was a composite outcome criteria including death or ICU admission at day 21 after admission. Threshold values of adipose tissue components predicting adverse outcome were determined., Results: One hundred and eight controls [median age: 76(IQR:59-83), 61% male, median BMI: 24(22-27)] and ninety-four T2D patients [median age: 70(IQR:61-77), 70% male, median BMI: 27(24-31)], were enrolled in this study. At day 21 after admission, 42 patients (21%) had died from COVID-19, 48 (24%) required intensive care and 112 (55%) were admitted to a conventional care unit (CMU). In T2D, CATi was associated with early death or ICU independently from age, sex, BMI, dyslipidemia, CRP and coronary calcium (CAC). (p = 0.005). Concerning T2D patients, the cut-point for CATi was  > 100 mL/m 2 with a sensitivity of 0.83 and a specificity of 0.50 (AUC = 0.67, p = 0.004) and an OR of 4.71 for early ICU admission or mortality (p = 0.002) in the fully adjusted model. Other adipose tissues SATi or VATi were not significantly associated with early adverse outcomes. In control patients, age and male sex (OR = 1.03, p = 0.04) were the only predictors of ICU or death., Conclusions: Cardiac adipose tissue volume measured in CT at admission was independently predictive of early intensive care or death in T2D patients with COVID-19 but not in non-diabetics. Such automated CT measurement could be used in routine in diabetic patients presenting with moderate to severe COVID-19 illness to optimize individual management and prevent critical evolution., (© 2022. The Author(s).)

Competing Interests: Competing interests: None declared.

Background: Lung reactivations of Herpesviridae, herpes simplex virus (HSV) and cytomegalovirus (CMV) have been reported in COVID-19 patients. Whether or not those viral reactivations are more frequent than in other patients is not known., Methods: Retrospective monocentric cohort study of 145 patients with severe COVID-19 pneumonia requiring invasive mechanical ventilation and who were tested for HSV and CMV in bronchoalveolar lavage performed during fiberoptic bronchoscopy for ventilator-associated pneumonia suspicion. Rates of HSV and CMV lung reactivations, and HSV bronchopneumonitis were assessed and compared with an historical cohort of 89 patients with severe influenza pneumonia requiring invasive mechanical ventilation., Results: Among the 145 COVID-19 patients included, 50% and 42% had HSV and CMV lung reactivations, respectively, whereas among the 89 influenza patients, 63% and 28% had HSV and CMV lung reactivations, respectively. Cumulative incidence of HSV lung reactivation (taking into account extubation and death as competing events) was higher in influenza than in COVID-19 patients (p = 0.03), whereas the rate of HSV bronchopneumonitis was similar in both groups (31% and 25%, respectively). Cumulative incidence of CMV lung reactivation (taking into account extubation and death as competing events) was similar in COVID-19 and influenza patients (p = 0.07). Outcomes of patients with HSV or CMV lung reactivations were similar to that of patients without, whatever the underlying conditions, i.e., in COVID-19 patients, in influenza patients, or when all patients were grouped., Conclusions: HSV and CMV lung reactivations are frequent in COVID-19 patients, but not more frequent than in patients with influenza-associated severe pneumonia, despite a higher severity of illness at intensive care unit admission of the latter and a longer duration of mechanical ventilation of the former. Although no impact on outcome of HSV and CMV lung reactivations was detected, the effect of antiviral treatment against these Herpesviridae remains to be determined in these patients., (© 2022. The Author(s).)

Objectives: Systemic rheumatic diseases (SRDs) are a group of inflammatory disorders that can need intensive care unit (ICU) admission during a flare-up, requiring administration of immunosuppressants. We undertook this study to determine the frequency, outcome, and occurrence associated factors of infections in flare-up SRD patients receiving immunosuppressant., Methods: Monocenter, a retrospective study including SRD patients admitted to ICU for a flare-up requiring immunosuppressant from 2004 to 2019. The primary endpoint was in-ICU-acquired infections., Results: Ninety-eight patients (female/male ratio: 1.6; mean age at admission: 39.5 ± 17.4 years) were admitted to the ICU for a SRD flare-up, inaugural in 61.2% cases. A specific treatment was given to every patient: corticosteroids 100%, cyclophosphamide 45.9%, plasma exchange 46.9%. Ninety-five infections occurred in 35 (36%) patients mainly pneumonias. The overall in-hospital mortality was 17.3%, and 46% of patients with a nosocomial infection died during their ICU stay. The logistic regression multivariable model retained renal replacement therapy and mechanical ventilation as independent predictors of infection., Conclusion: In-ICU-acquired infection in SRD flare-up is a frequent event associated with organ failures but not with in-ICU use of immunosuppressants. These data suggest that the fear of infection should not withhold a careful in-ICU use of immunosuppressive drugs. Key Points • In-ICU infections are frequent in flare-up systemic rheumatic disease patients. • Infections are associated with increased mortality. • Cyclophosphamide given in ICU was not independently associated with infection. • Severe neutropenia occurred in 27% of patients receiving cyclophosphamide in ICU., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe., Methods: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM., Results: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia ( P =0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P <0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%)., Conclusions: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe hemodynamic compromise secondary to acute myocardial inflammation, often presenting as profound cardiogenic shock, life-threatening ventricular arrhythmias and/or electrical storm. FM may be refractory to conventional therapies and require mechanical circulatory support (MCS). The immune system has been recognized as playing a pivotal role in the pathophysiology of myocarditis, leading to an increased focus on immunosuppressive treatment strategies. Recent data have highlighted not only the fact that FM has significantly worse outcomes than non-FM, but that prognosis and management strategies of FM are heavily dependent on histological subtype, placing greater emphasis on the role of endomyocardial biopsy in diagnosis. The impact of subtype on severity and prognosis will likewise influence how aggressively the myocarditis is managed, including whether MCS is warranted. Many patients with refractory cardiogenic shock secondary to FM end up requiring MCS, with venoarterial extracorporeal membrane oxygenation demonstrating favorable survival rates, particularly when initiated prior to the development of multiorgan failure. Among the challenges facing the field are the need to more precisely identify immunopathophysiological pathways in order to develop targeted therapies, and the need to better optimize the timing and management of MCS to minimize complications and maximize outcomes., (Copyright and License information: Journal of Geriatric Cardiology 2022.)

Objectives: To determine the characteristics and outcomes of patients prone-positioned during extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and lung CT pattern associated with improved respiratory system static compliance after that intervention., Design: Retrospective, single-center study over 8 years., Settings: Twenty-six bed ICU in a tertiary center., Measurements and Main Results: A propensity score-matched analysis compared patients with prone-positioning during extracorporeal membrane oxygenation and those without. An increase of the static compliance greater than or equal to 3 mL/cm H2O after 16 hours of prone-positioning defined prone-positioning responders. The primary outcome was the time to successful extracorporeal membrane oxygenation weaning within 90 days of postextracorporeal membrane oxygenation start, with death as a competing risk. Among 298 venovenous extracorporeal membrane oxygenation-treated adults with severe acute respiratory distress syndrome, 64 were prone-positioning extracorporeal membrane oxygenation. Although both propensity score-matched groups had similar extracorporeal membrane oxygenation durations, prone-positioning extracorporeal membrane oxygenation patients' 90-day probability of being weaned-off extracorporeal membrane oxygenation and alive was higher (0.75 vs 0.54, p = 0.03; subdistribution hazard ratio [95% CI], 1.54 [1.05-2.58]) and 90-day mortality was lower (20% vs 42%, p < 0.01) than that for no prone-positioning extracorporeal membrane oxygenation patients. Extracorporeal membrane oxygenation-related complications were comparable for the two groups. Patients without improved static compliance had higher percentages of nonaerated or poorly aerated ventral and medial-ventral lung regions (p = 0.047)., Conclusions: Prone-positioning during venovenous extracorporeal membrane oxygenation was safe and effective and was associated with a higher probability of surviving and being weaned-off extracorporeal membrane oxygenation at 90 days. Patients with greater normally aerated lung tissue in the ventral and medial-ventral regions on quantitative lung CT-scan performed before prone-positioning are more likely to improve their static compliance after that procedure during extracorporeal membrane oxygenation., Competing Interests: Dr. Combes received grants from Getinge and personal fees from Getinge, Baxter, and Xenios outside the submitted work. Dr. Schmidt received personal fees from Getinge, Drager, 3M, and Xenios, outside the submitted work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 [interquartile range: 10; 23] days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis., (© 2022. The Author(s).)

Background: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients., Methods: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2., Results: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs)., Conclusion: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: The data on incidence, clinical presentation, and outcomes of ventilator-associated pneumonia (VAP) in patients with severe coronavirus disease 2019 (COVID-19) pneumonia requiring mechanical ventilation (MV) are limited. We performed this retrospective cohort study to assess frequency, clinical characteristics, responsible pathogens, and outcomes of VAP in patients COVID-19 pneumonia requiring MV between March 12th and April 24th, 2020 (all had RT-PCR-confirmed SARS-CoV-2 infection). Patients with COVID-19-associated acute respiratory distress syndrome (ARDS) requiring ECMO were compared with an historical cohort of 45 patients with severe influenza-associated ARDS requiring ECMO admitted to the same ICU during the preceding three winter seasons., Results: Among 50 consecutive patients with Covid-19-associated ARDS requiring ECMO included [median (IQR) age 48 (42-56) years; 72% male], 43 (86%) developed VAP [median (IQR) MV duration before the first episode, 10 (8-16) days]. VAP-causative pathogens were predominantly Enterobacteriaceae (70%), particularly inducible AmpC-cephalosporinase producers (40%), followed by Pseudomonas aeruginosa (37%). VAP recurred in 34 (79%) patients and 17 (34%) died. Most recurrences were relapses (i.e., infection with the same pathogen), with a high percentage occurring on adequate antimicrobial treatment. Estimated cumulative incidence of VAP, taking into account death and extubation as competing events, was significantly higher in Covid-19 patients than in influenza patients (p = 0.002). Despite a high P. aeruginosa-VAP rate in patients with influenza-associated ARDS (54%), the pulmonary infection recurrence rate was significantly lower than in Covid-19 patients. Overall mortality was similar for the two groups., Conclusions: Patients with severe Covid-19-associated ARDS requiring ECMO had a very high late-onset VAP rate. Inducible AmpC-cephalosporinase-producing Enterobacteriaceae and Pseudomonas aeruginosa frequently caused VAP, with multiple recurrences and difficulties eradicating the pathogen from the lung.

Background: Prone positioning (PP) during veno-venous ECMO is feasible, but its physiological effects have never been thoroughly evaluated. Our objectives were to describe, through electrical impedance tomography (EIT), the impact of PP on global and regional ventilation, and optimal PEEP level., Methods: A monocentric study conducted on ECMO-supported severe ARDS patients, ventilated in pressure-controlled mode, with 14-cmH 2 O driving pressure and EIT-based "optimal PEEP". Before, during and after a 16-h PP session, EIT-based distribution and variation of tidal impedance, VT dorsal /VT global ratio, end-expiratory lung impedance (EELI) and static compliance were collected. Subgroup analyses were performed in patients who increased their static compliance by ≥ 3 mL/cmH 2 O after 16 h of PP., Results: For all patients (n = 21), tidal volume and EELI were redistributed from ventral to dorsal regions during PP. EIT-based optimal PEEP was significantly lower in PP than in supine position. Median (IQR) optimal PEEP decreased from 14 (12-16) to 10 (8-14) cmH 2 O. Thirteen (62%) patients increased their static compliance by ≥ 3 mL/cmH 2 O after PP on ECMO. This subgroup had higher body mass index, more frequent viral pneumonia, shorter ECMO duration, and lower baseline VT dorsal /VT global ratio than patients with compliance ≤ 3 mL/cmH 2 O (P < 0.01)., Conclusion: Although baseline tidal volume distribution on EIT may predict static compliance improvement after PP on ECMO, our results support physiological benefits of PP in all ECMO patients, by modifying lung mechanics and potentially reducing VILI. Further studies, including a randomized-controlled trial, are now warranted to confirm potential PP benefits during ECMO.