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Purpose: COVID-19 associated pulmonary aspergillosis (CAPA) is associated with increased morbidity and mortality in ICU patients. We investigated the incidence of, risk factors for and potential benefit of a pre-emptive screening strategy for CAPA in ICUs in the Netherlands/Belgium during immunosuppressive COVID-19 treatment., Materials and Methods: A retrospective, observational, multicentre study was performed from September 2020-April 2021 including patients admitted to the ICU who had undergone diagnostics for CAPA. Patients were classified based on 2020 ECMM/ISHAM consensus criteria., Results: CAPA was diagnosed in 295/1977 (14.9%) patients. Corticosteroids were administered to 97.1% of patients and interleukin-6 inhibitors (anti-IL-6) to 23.5%. EORTC/MSGERC host factors or treatment with anti-IL-6 with or without corticosteroids were not risk factors for CAPA. Ninety-day mortality was 65.3% (145/222) in patients with CAPA compared to 53.7% (176/328) without CAPA (p = 0.008). Median time from ICU admission to CAPA diagnosis was 12 days. Pre-emptive screening for CAPA was not associated with earlier diagnosis or reduced mortality compared to a reactive diagnostic strategy., Conclusions: CAPA is an indicator of a protracted course of a COVID-19 infection. No benefit of pre-emptive screening was observed, but prospective studies comparing pre-defined strategies would be required to confirm this observation., Competing Interests: Declaration of Competing Interest Paul Verweij: Institution contracted for research grant: F2G and Gilead Sciences; Honoraria for lectures paid to institution: F2G, Gilead Sciences, Pfizer; Participation on a Data Safety Monitoring Board or Advisory Board paid to institution: F2G, Mundipharma. Roger Brüggeman: Institution contracted for research grant: Astellas Pharma, Inc., Gilead Sciences, Merck Sharp & Dohme Corp., Pfizer; Consulting fees paid to institution: Astellas Pharma, Inc., F2G, Amplyx, Gilead Sciences, Merck Sharp & Dohme Corp., Mundipharma, Pfizer. Joost Wauters: Investigator-initiated grants: Gilead, MSD, Pfizer; Consulting fees: Investigator-initiated grants from Gilead, Pfizer; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Speakers fees from Gilead, Pfizer; Support for attending meetings and/or travel: travel grants from Gilead and Pfizer. No potential financial or non-financial competing interest was reported by any of the other authors., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Nephrotoxic drugs frequently cause acute kidney injury (AKI) in adult intensive care unit (ICU) patients. However, there is a lack of large pharmaco-epidemiological studies investigating the associations between drugs and AKI. Importantly, AKI risk factors may also be indications or contraindications for drugs and thereby confound the associations. Here, we aimed to estimate the associations between commonly administered (potentially) nephrotoxic drug groups and AKI in adult ICU patients whilst adjusting for confounding., Methods: In this multicenter retrospective observational study, we included adult ICU admissions to 13 Dutch ICUs. We measured exposure to 44 predefined (potentially) nephrotoxic drug groups. The outcome was AKI during ICU admission. The association between each drug group and AKI was estimated using etiological cause-specific Cox proportional hazard models and adjusted for confounding. To facilitate an (independent) informed assessment of residual confounding, we manually identified drug group-specific confounders using a large drug knowledge database and existing literature., Results: We included 92 616 ICU admissions, of which 13 492 developed AKI (15%). We found 14 drug groups to be associated with a higher hazard of AKI after adjustment for confounding. These groups included established (e.g. aminoglycosides), less well established (e.g. opioids) and controversial (e.g. sympathomimetics with α- and β-effect) drugs., Conclusions: The results confirm existing insights and provide new ones regarding drug associated AKI in adult ICU patients. These insights warrant caution and extra monitoring when prescribing nephrotoxic drugs in the ICU and indicate which drug groups require further investigation., Competing Interests: The authors declare that they have no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease-associated pulmonary aspergillosis (CAPA). We found 10%-15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%-52%.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy. Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response. The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy., Methods: This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands. With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020. In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course., Findings: Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41-78). Median disease course (time from onset of symptoms to death) was 22 days (range 5-44 days). In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course. Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata. Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5-44]; ten patients with neutrophilic plugs, 21 days [5-44]). Neutrophilic plugs were observed in two forms: solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets.., Interpretation: In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19., Funding: Amsterdam UMC Corona Research Fund., (© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.)

High-dose methotrexate (MTX) induced acute kidney injury can lead to sustained high systemic MTX levels and severe toxicity. A 39-year-old man with lymphoblastic T-cell lymphoma was admitted to our intensive care unit with elevated serum creatinine and prolonged high serum MTX levels. Standard supportive care was complemented by the addition of a relatively novel agent, glucarpidase, which rapidly lowered the extracellular levels of MTX. Several case series support this effect of glucarpidase, but no randomised controlled trial has been performed to show this leads to better outcome. Furthermore, glucarpidase might negatively affect leucovorin rescue therapy. Lastly, glucarpidase carries a significant financial burden. Based on the current evidence we cannot recommend glucarpidase until further research elucidates its role in the treatment of MTX toxicity. There is no randomised clinical evidence to support its use in severe cases and theoretical evidence suggests that after prolonged exposure to high MTX levels glucarpidase administration is unable to reverse high intracellular MTX. We recommend that new randomised controlled studies be aimed at early administration of glucarpidase in patients with high MTX levels shortly after administration to prevent direct toxic effects of MTX on kidney function and further uptake into cells.

Objective: Acute kidney injury (AKI) is a serious complication after repair of a ruptured abdominal aortic aneurysm (RAAA). In the present Society for Vascular Surgery (SVS)/International Society for CardioVascular Surgery (ISCVS) reporting standards patients are classified as no dialysis (grade I), as temporary dialysis (grade II), and as permanent dialysis or fatal outcome (grade III). However, AKI is a broad clinical syndrome including more than the requirement for renal replacement therapy. The recently introduced 'Risk,' 'Injury,' 'Failure,' 'Loss,' and 'End-stage' (RIFLE) classification for AKI comprises three severity categories based on serum creatinine and urine output ('Risk,' 'Injury,' and 'Failure'). The objective of the present study was to assess the incidence of AKI using the RIFLE criteria (AKIRIFLE). Secondary objectives were to assess the incidence of AKI as defined using the SVS/ISCVS reporting standards (AKISVS/ISCVS) and the association between AKIRIFLE and death., Methods: This was an observational cohort study in 362 consecutive patients with an RAAA in three hospitals in Amsterdam (The Netherlands) between 2004 and 2011. The end points were the incidence of AKIRIFLE, of AKISVS/ISCVS, and the combined 30-day or in-hospital death rate. A multivariable logistic regression model was made to assess the association between AKIRIFLE and death after adjustment for preoperative shock profile (Glasgow Aneurysm Score) and postoperative shock profile (Acute Physiology and Chronic Health Evaluation [APACHE] II score, use of vasopressors, and fluid balance during the first 24 hours after intervention)., Results: AKIRIFLE occurred in 74% (267/362; 95% confidence interval [CI], 69%-78%), with 27% of these patients categorized as 'Risk' (71/267; 95% CI, 22%-32%), 39% categorized as 'Injury' (104/267, 95% CI, 33%-45%), and 34% categorized as 'Failure' (92/267; 95% CI, 29%-40%). AKISVS/ISCVS occurred in 48% (175/362; 95% CI, 43%-53%), with 53% of these categorized as 'grade I' (92/175; 95% CI, 45%-60%), 19% as 'grade II' (34/175; 95% CI, 14%-26%), and 28% as 'grade III' (49/175; 95% CI, 22%-35%). After multivariable adjustment for shock profiles the risk of dying in patients categorized as AKIRIFLE 'Failure' was greater than in patients without AKIRIFLE (adjusted odds ratio, 6.360; 95% CI, 2.231-18.130)., Conclusions: The incidence of AKI defined according to the RIFLE criteria (74%) was greater than defined using the SVS/ISCVS reporting standards (48%) and patients categorized as 'Failure' using the RIFLE criteria had a greater risk of dying than patients without AKI. These results indicate that the problem of AKI is much bigger than previously anticipated and that minimizing injury to the kidney could be an important focus of future research on reducing the death rate after RAAA repair., (Copyright © 2014 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)