PURPOSE OF REVIEW:Liver dysfunction is a frequent yet underrecognized feature of critical illness, affecting up to 20-40% of ICU patients. Even mild abnormalities in liver function tests are associated with increased morbidity, prolonged ICU stay, and higher mortality. Hepatic dysfunction may be the primary reason for ICU admission or develop during the ICU stay. Its clinical presentation is broad, ranging from abnormal liver function tests due to sepsis, drug toxicity, or hypoxia during critical illness, to acute liver failure in previously healthy individuals, and acute-on-chronic liver failure in patients with preexisting liver disease. RECENT FINDINGS:Recent advances highlight the importance of dynamic liver function testing, such as indocyanine green clearance, in early detection and prognostication. Moreover, evolving concepts around acute-on-chronic liver failure (ACLF) emphasize its systemic nature and the need for timely intervention, including liver support therapies and transplantation. Understanding the interplay between hepatic dysfunction and multiorgan failure is essential for improving outcomes in this vulnerable population. SUMMARY:This review highlights recent advances in understanding into the mechanisms, diagnosis, and management of liver dysfunction in critically ill patients, with a particular emphasis on ACLF.

Herpes simplex virus type 1 (HSV-1) and cytomegalovirus (CMV) are frequently detected in respiratory samples from patients with acute respiratory distress syndrome (ARDS), yet whether PCR positivity reflects histologically confirmed pulmonary infection and contributes to lung injury remains unclear. We aimed to characterize the histopathological features of pulmonary HSV-1 and CMV using PCR and immunohistochemistry on lung tissue specimens of critically ill patients with influenza- or COVID-19-related ARDS obtained at autopsy. In addition, we sought to correlate pulmonary herpesvirus loads in antemortem bronchoalveolar lavage fluid (BALF) samples with postmortem histological findings. In this retrospective autopsy cohort, we included patients with COVID-19- or influenza-related ARDS who died in the intensive care unit and underwent autopsy between 2009 and 2021. Lung tissue blocks were systematically screened for HSV-1 and CMV using PCR and immunohistochemistry. Performance of HSV-1 PCR on BALF for diagnosing proven HSV-1 infection was evaluated with receiver operating characteristic analysis. We included 22 patients with COVID-19- and 20 with influenza-related ARDS. Proven HSV-1-associated necrotizing tracheobronchitis was identified in 6/42 patients (14

BACKGROUND:As compared to withholding parenteral nutrition (PN) until one week after intensive care unit (ICU) admission, Early PN prolonged ICU dependency in the EPaNIC randomized controlled trial (RCT). The Refeeding RCT showed improved outcome by temporary macronutrient restriction in ICU patients developing refeeding hypophosphatemia, defined as a phosphate decrease of > 0.16 mmol/L to levels < 0.65 mmol/L. We hypothesized that early phosphate changes may identify critically ill patients who are harmed by Early PN, and that dynamic phosphate changes are more discriminative than an absolute threshold for hypophosphatemia. METHODS:In this secondary analysis of the EPaNIC RCT, we studied whether absolute hypophosphatemia (AHP; < 0.65 mmol/L on the second ICU-day), relative hypophosphatemia (RHP; > 0.16 mmol/L decrease over the first 2 ICU-days), or a combination of both (CHP) interacted with the randomized nutritional strategy for its impact on outcome, adjusted for risk factors. In case of significant interaction, we studied whether the respective change could be predicted by baseline characteristics. RESULTS:Of 3520 patients with available phosphate measurements, AHP developed in 9.1%, RHP in 23.7%, and CHP in 5.3% of patients. RHP, but not AHP or CHP, interacted with the randomized intervention for its impact on outcome (p = 0.01). In RHP patients, Early PN independently associated with a lower likelihood of an earlier discharge alive from ICU (adjusted HR 0.75 [0.65-0.87]). In patients without RHP, Early PN did not significantly associate with this outcome (adjusted HR 0.93 [0.86-1.00]). Development of RHP was only poorly predicted by admission characteristics (adjusted pseudo R-squared = 1.7%). CONCLUSION:Development of RHP may identify patients who are particularly harmed by early PN. Future studies should prospectively validate the potential of including RHP in a ready-to-feed indicator.

Our case describes an apparently immunocompetent patient in the intensive care unit (ICU) with a non-resolving pneumonia despite antibiotic treatment. On bronchoalveolar lavage (BAL), a positive herpes simplex virus (HSV) PCR was obtained, which was left untreated because of the absence of underlying immunosuppression. However, postmortem analysis revealed a necrotising pneumonia due to massive HSV reactivation. Our case highlights the importance of HSV as a potential pathogen in the ICU, even in apparently immunocompetent individuals. Moreover, this article underscores the absence of clear guidelines in the current literature regarding HSV management in critically ill patients.

ECMO outcomes in COVID-19-related respiratory failure among solid organ transplant (SOT) and hematopoietic stem-cell transplant recipients (HSCT) are poorly described. We investigated: (1) whether transplant patients (SOT/HSCT) with COVID-19 have worse outcomes than non-immunocompromised (IC) COVID-19 patients, and (2) whether among transplant recipients (SOT/HSCT), those with COVID-19 have worse outcomes than those with non-COVID-19-related respiratory failure. Additionally, we aimed to identify factors independently associated with mortality among COVID-19 transplants. Retrospective analyses of the Extracorporeal Life Support Organization Registry from 1/1/2017 to 31/07/2023. Two comparisons were made: (1) transplant COVID-19 versus non-IC COVID-19, and (2) transplant COVID-19 versus transplant non-COVID-19 patients. Outcomes were analyzed using propensity score (PS)-adjusted, multivariable, and PS-matched analyses, adjusting for a priori identified confounders. Primary outcome was in-hospital mortality. Among 38,270 runs, 146 transplant COVID-19, 12,552 non-IC-COVID-19 and 886 transplant non-COVID-19 runs were identified. In-hospital mortality in transplant COVID-19 patients was 75.3

BACKGROUND AND AIMS:Steroid supplementation remains controversial in septic shock, partly due to the heterogeneity of the populations studied. Cirrhotic patients with sepsis frequently develop relative adrenal insufficiency, showing poor response to vasopressors and poor prognosis. Early administration of low-dose hydrocortisone might facilitate shock reversal and reduce mortality in this population. METHODS:Double-blind, randomised, placebo-controlled multicentre trial, enrolling adult cirrhotic patients with septic shock. Patients were assigned to receive i.v. hydrocortisone (100 mg followed by a continuous infusion of 200 mg/24 h) or placebo, for at least 3 days, followed by a tapering period of 3-7 days, depending on the time of shock resolution. Primary endpoint was 28-day all-cause mortality. RESULTS:After enrolment of 83 patients the trial was stopped early due to slow inclusions. Most patients required low-to-moderate doses of vasopressors. There was no difference in 28-day mortality (35% vs. 39.5%; p = 0.84) between hydrocortisone and placebo groups. Shock resolution (85% vs. 72.1%; p = 0.25) and days to shock resolution [3 days (2.2-4; IQR) vs. 4 (2-7.5; IQR)] were also similar between groups. More patients receiving placebo died of refractory shock (47.6% vs. 8.7%). No significant differences between treatment arms were observed in shock relapse, new shock episodes or bacterial or fungal superinfections during hospital stay. Hypo- and hyperglycaemias were more frequent in the hydrocortisone arm. Severity of ACLF at inclusion and inadequacy of empirical antibiotic therapy (HR = 6.40; 95% CI: 3.21-12.79) independently predicted 28-day mortality. CONCLUSIONS:Supplemental hydrocortisone did not improve short-term survival in cirrhotic patients with septic shock requiring low-to-moderate doses of vasopressors. TRIAL REGISTRATION:S-number University Hospitals Leuven, Belgium: S55168; EUDRACT: 2010-024273-38; Clinicaltrials.gov id: NCT02602210.

Background and Aims: Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and nonrecovery in ACLF. Approach and Results: Here, we mapped the single-cell transcriptome of circulating immune cells from patients with ACLF and acute decompensated (AD) cirrhosis and healthy individuals. We further interrogate how these findings, as well as immunometabolic and functional profiles, associate with ACLF-recovery (ACLF-R) or nonrecovery (ACLF-NR). Our analysis unveiled 2 distinct states of classical monocytes (cMons). Hereto, ACLF-R cMons were characterized by transcripts associated with immune and stress tolerance, including anti-inflammatory genes such as RETN and LGALS1. Additional metabolomic and functional validation experiments implicated an elevated oxidative phosphorylation metabolic program as well as an impaired ACLF-R cMon functionality. Interestingly, we observed a common stress-induced tolerant state, oxidative phosphorylation program, and blunted activation among lymphoid populations in patients with ACLF-R. Conversely, ACLF-NR cMon featured elevated expression of inflammatory and stress response genes such as VIM, LGALS2, and TREM1, along with blunted metabolic activity and increased functionality. Conclusions: This study identifies distinct immunometabolic cellular states that contribute to disease outcomes in patients with ACLF. Our findings provide valuable insights into the pathogenesis of ACLF, shedding light on factors driving either recovery or nonrecovery phenotypes, which may be harnessed as potential therapeutic targets in the future.

Introduction and Objectives. TIPS placement is an effective, possibly life-saving, treatment for complications of portal hypertension. The pressure shift induced by the stent can lead to cardiac decompensation (CD). We investigated the incidence of CD, possible variables associated with CD and the validity of the Toulouse algorithm for risk prediction of CD post-TIPS.Patients and Methods. A total of 106 patients receiving TIPS for variceal bleeding (VB, 41.5%) or refractory ascites (RA, 58.5%) with available echocardiography and NT-proBNP results were included and retrospectively reviewed. Development of CD between time of TIPS placement and occurrence of liver transplantation, death or loss-to-follow-up was recorded. Competing risk regression analysis was performed to assess which baseline variables predicted occurrence of CD post-TIPS.Results. A total of 12 patients (11.3%) developed CD after a median of 11.5 days (IQR 4 to 56.5) post-TIPS. Multivariate regression showed age (HR 1.06, p=0.019), albumin (HR 1.10, p=0.009) and NT-proBNP (HR 1.00, p=0.023) at baseline predicted CD in the RA group. No clear predictors were found in those receiving TIPS for VB. Correspondingly, the Toulouse algorithm successfully identified patients at risk for CD, however only in the RA population (zero risk 0% vs. low risk 12.5% vs. high risk 35.3% with CD; p=0.003).Conclusions. CD is not an infrequent complication post-TIPS occurring in 1/10 patients. The Toulouse algorithm can identify patients at risk of CD, though only in patients receiving TIPS for RA. Allocation to the high-risk category warrants close monitoring but should not preclude TIPS placement.

BACKGROUND:Sarcopenia is an acknowledged risk factor for individuals with chronic liver disease, however, the influence on outcomes in patients receiving transjugular intrahepatic portosystemic shunt (TIPS) remains underexplored. AIMS:This study aimed to investigate the association between sarcopenia and incidence of complications and mortality post-TIPS. METHODS:A retrospective analysis was performed on 175 patients who underwent TIPS between 2011-2021 at a Belgian tertiary care center. Transverse psoas muscle thickness (TPMT) was measured at baseline, with a subset of 85 patients having a second TPMT after 1-2 years for assessment of evolution. RESULTS:Over a median follow-up of 453 days (IQR 76-1179), sarcopenic patients exhibited a higher prevalence of complications (74.1% vs. 57.9%, p = 0.04) and one-year mortality (53.4% vs. 22.3%, p < 0.001) post-TIPS. Notably, 58.8% of patients showed an increase >10% from baseline TPMT/length post-TIPS, with the greatest improvement observed in severely sarcopenic patients (4.00 ± 4.55 mm/m vs. -0.82 ± 2.68 mm/m, p < 0.001) and in those patients free from TIPS-related complications (3.18 ± 4.09 mm/m vs. 1.31 ± 3.21 mm/m, p = 0.022). CONCLUSION:Sarcopenia increases the risk of complications and mortality post-TIPS. Importantly, sarcopenia improves in patients receiving TIPS, particularly in those with severe sarcopenia at baseline and free of TIPS-related complications.

Background This study evaluated the technical and clinical outcomes of transcatheter arterial embolization (TAE) in patients with acute small-bowel bleeding (SBB) and aimed to identify potential risk factors for early recurrent bleeding after TAE. Methods Thirty-one patients with SBB managed with TAE between January 2006 and December 2021 were included. Technical and clinical success was defined as angiographic occlusion of the bleeding artery and disappearance of clinical or laboratory signs of persistent bleeding without major complications. Complications were classified according to the Society of Interventional Radiology's guidelines. Kaplan-Meier estimates assessed overall survival, and logistic regression models determined risk factors for clinical success and early rebleeding. Results Technical and clinical success were achieved in 30/31 (97%) and 19 (61%), respectively. Early recurrent bleeding was present in 9 (29%) patients, and was treated by repeat embolization in 4 patients, conversion to surgery in 4, and comfort therapy in 1 patient. TAE-related small bowel ischemia requiring surgery was found in 2 (6.5%) patients. Thirty-day and in-hospital mortality were 19% (6/31) and 23% (7/31), respectively; overall 5-year estimated survival was 60%. Thrombocytopenia and elevated prothrombin time (PT)/activated partial thromboplastin time (aPTT) levels prior to TAE were identified as risk factors for clinical failure (P=0.0026 and P=0.027, respectively), and for residual or early recurrent bleeding (P<0.001 and P=0.01, respectively). Conclusions TAE is safe and effective for managing severe SBB; however, early recurrent bleeding was found in nearly one third of patients. Thrombocytopenia and elevated PT/aPTT levels were risk factors for early recurrent bleeding.

Rationale: The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza-associated pulmonary aspergillosis (IAPA) or coronavirus disease (COVID-19)-associated pulmonary aspergillosis (CAPA) has yet to be explored. Objectives: To explore the composition of the lung bacterial microbiome and its association with viral and fungal infection, immunity, and outcome in severe influenza versus COVID-19 with or without aspergillosis. Methods: We performed a retrospective study in mechanically ventilated patients with influenza and COVID-19 with or without invasive aspergillosis in whom BAL for bacterial culture (with or without PCR) was obtained within 2 weeks after ICU admission. In addition, 16S rRNA gene sequencing data and viral and bacterial load of BAL samples from a subset of these patients, and of patients requiring noninvasive ventilation, were analyzed. We integrated 16S rRNA gene sequencing data with existing immune parameter datasets. Measurements and Main Results: Potential bacterial pathogens were detected in 20% (28/142) of patients with influenza and 37% (104/281) of patients with COVID-19, whereas aspergillosis was detected in 38% (54/142) of patients with influenza and 31% (86/281) of patients with COVID-19. A significant association between bacterial pathogens in BAL fluid and 90-day mortality was found only in patients with influenza, particularly patients with IAPA. Patients with COVID-19, but not patients with influenza, showed increased proinflammatory pulmonary cytokine responses to bacterial pathogens. Conclusions: Aspergillosis is more frequently detected in the lungs of patients with severe influenza than bacterial pathogens. Detection of bacterial pathogens associates with worse outcome in patients with influenza, particularly in those with IAPA, but not in patients with COVID-19. The immunological dynamics of tripartite viral-fungal-bacterial interactions deserve further investigation.

Background Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a frequent superinfection in critically ill patients with COVID-19 and is associated with increased mortality rates. The increasing proportion of severely immunocompromised patients with COVID-19 who require mechanical ventilation warrants research into the incidence and impact of CAPA during the vaccination era.Methods We performed a retrospective, monocentric, observational study. We collected data from adult patients with severe COVID-19 requiring mechanical ventilation who were admitted to the intensive care unit (ICU) of University Hospitals Leuven, a tertiary referral center, between 1 March 2020 and 14 November 2022. Probable or proven CAPA was diagnosed according to the 2020 European Confederation for Medical Mycology/International Society for Human and Animal Mycology (ECMM/ISHAM) criteria.Results We included 335 patients. Bronchoalveolar lavage sampling was performed in 300 (90%), and CAPA was diagnosed in 112 (33%). The incidence of CAPA was 62% (50 of 81 patients) in European Organisation for Research and Treatment of Cancer (EORTC)/Mycosis Study Group Education and Research Consortium (MSGERC) host factor-positive patients, compared with 24% (62 of 254) in host factor-negative patients. The incidence of CAPA was significantly higher in the vaccination era, increasing from 24% (57 of 241) in patients admitted to the ICU before October 2021 to 59% (55 of 94) in those admitted since then. Both EORTC/MSGERC host factors and ICU admission in the vaccination era were independently associated with CAPA development. CAPA remained an independent risk factor associated with mortality risk during the vaccination era.Conclusions The presence of EORTC/MSGERC host factors for invasive mold disease is associated with increased CAPA incidence and worse outcome parameters, and it is the main driver for the significantly higher incidence of CAPA in the vaccination era. Our findings warrant investigation of antifungal prophylaxis in critically ill patients with COVID-19. The incidence of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) increased significantly in mechanically ventilated patients with COVID-19 as the proportion of severely immunocompromised patients increased since widespread vaccination. CAPA stays independently associated with mortality rate in the vaccination era. Graphical Abstract https://tidbitapp.io/tidbits/high-burden-of-covid-19-associated-pulmonary-aspergillosis-capa-in-severelyimmunocompromised-patients-requiring-mechanical-ventilation

BACKGROUND:COVID-19-associated pulmonary aspergillosis (CAPA) is a severe superinfection with the fungus Aspergillus affecting patients who are critically ill with COVID-19. The pathophysiology and the role of neutrophil extracellular traps (NETs) in this infection are largely unknown. We aimed to characterise the immune profile, with a focus on neutrophils and NET concentrations, of critically ill patients with COVID-19, with or without CAPA. METHODS:We conducted a single-centre, retrospective, observational study in two patient cohorts, both recruited at University Hospitals Leuven, Belgium. We included adults aged 18 years or older who were admitted to the intensive care unit because of COVID-19 between March 31, 2020, and May 18, 2021, and who were included in the previous Contagious trial (NCT04327570). We investigated the immune cellular landscape of CAPA versus COVID-19 only by performing single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid. Bronchoalveolar lavage immune cell fractions were compared between patients with CAPA and patients with COVID-19 only. Additionally, we determined lower respiratory tract NET concentrations using biochemical assays in patients aged 18 years and older who were admitted to the intensive care unit because of severe COVID-19 between March 15, 2020, and Dec 31, 2021, for whom bronchoalveolar lavage was available in the hospital biobank. Bronchoalveolar lavage NET concentrations were compared between patients with CAPA and patients with COVID-19 only and integrated with existing data on immune mediators in bronchoalveolar lavage and 90-day mortality. FINDINGS:We performed scRNA-seq of bronchoalveolar lavage on 43 samples from 39 patients, of whom 36 patients (30 male and six female; 14 with CAPA) were included in downstream analyses. We performed bronchoalveolar lavage NET analyses in 59 patients (46 male and 13 female), of whom 26 had CAPA. By scRNA-seq, patients with CAPA had significantly lower neutrophil fractions than patients with COVID-19 only (16% vs 33%; p=0·0020). The remaining neutrophils in patients with CAPA preferentially followed a hybrid maturation trajectory characterised by expression of genes linked to antigen presentation, with enhanced transcription of antifungal effector pathways. Patients with CAPA also showed depletion of mucosal-associated invariant T cells, reduced T helper 1 and T helper 17 differentiation, and transcriptional defects in specific aspects of antifungal immunity in macrophages and monocytes. We observed increased formation of NETs in patients with CAPA compared with patients with COVID-19 only (DNA complexed with citrullinated histone H3 median 15 898 ng/mL [IQR 4588-86 419] vs 7062 ng/mL [775-14 088]; p=0·042), thereby explaining decreased neutrophil fractions by scRNA-seq. Low bronchoalveolar lavage NET concentrations were associated with increased 90-day mortality in patients with CAPA. INTERPRETATION:Qualitative and quantitative disturbances in monocyte, macrophage, B-cell, and T-cell populations could predispose patients with severe COVID-19 to develop CAPA. Hybrid neutrophils form a specialised response to CAPA, and an adequate neutrophil response to CAPA is a major determinant for survival in these patients. Therefore, measuring bronchoalveolar lavage NETs could have diagnostic and prognostic value in patients with CAPA. Clinicians should be wary of aspergillosis when using immunomodulatory therapy that might inhibit NETosis to treat patients with severe COVID-19. FUNDING:Research Foundation Flanders, KU Leuven, UZ Leuven, VIB, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, la Caixa Foundation, the Flemish Government, and Horizon 2020.