Publications by authors named "Jan Gunst"

72 Publications

C-reactive protein rise in response to macronutrient deficit early in critical illness: sign of inflammation or mediator of infection prevention and recovery.

Intensive Care Med 2021 Nov 24. Epub 2021 Nov 24.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Purpose: Withholding parenteral nutrition (PN) early in critical illness, late-PN, has shown to prevent infections despite a higher peak C-reactive protein (CRP). We investigated whether the accentuated CRP rise was caused by a systemic inflammatory effect mediated by cytokines or arose as a consequence of the different feeding regimens, and whether it related to improved outcome with late-PN.

Methods: This secondary analysis of the EPaNIC-RCT first investigated, with multivariable linear regression analyses, determinants of late-PN-induced CRP rise and its association with cytokine responses (IL-6, IL-10, TNF-α) in matched early-PN and late-PN patients requiring intensive care for ≥ 3 days. Secondly, with multivariable logistic regression and Cox proportional-hazard analyses, we investigated whether late-PN-induced CRP rises mediated infection prevention and enhanced recovery or reflected an adverse effect counteracting such benefits of late-PN.

Results: CRP peaked on day 3, higher with late-PN [216(152-274)mg/l] (n = 946) than with early-PN [181(122-239)mg/l] (n = 946) (p < 0.0001). Independent determinants of higher CRP rise were lower carbohydrate and protein intakes (p ≤ 0.04) with late-PN, besides higher blood glucose and serum insulin concentrations (p ≤ 0.01). Late-PN did not affect cytokines. Higher CRP rises were independently associated with more infections and lower likelihood of early ICU discharge (p ≤ 0.002), and the effect size of late-PN versus early-PN on these outcomes was increased rather than reduced after adjusting for CRP rise, not confirming a mediating role.

Conclusions: The higher CRP rise with late-PN, explained by the early macronutrient deficits, did not relate to cytokine responses and thus did not reflect more systemic inflammation. Instead of mediating clinical benefit on infection or recovery, the accentuated CRP rise appeared an adverse effect reducing such late-PN benefits.
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http://dx.doi.org/10.1007/s00134-021-06565-1DOI Listing
November 2021

Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb.

Cell 2021 11 3;184(24):5932-5949.e15. Epub 2021 Nov 3.

Department of Neurosciences, Experimental Otorhinolaryngology, Rhinology Research, KU Leuven, Leuven, Belgium; Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Unit, KU Leuven, Leuven, Belgium. Electronic address:

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.
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http://dx.doi.org/10.1016/j.cell.2021.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564600PMC
November 2021

Aerobic exercise capacity in long-term survivors of critical illness: secondary analysis of the post-EPaNIC follow-up study.

Intensive Care Med 2021 Dec 8;47(12):1462-1471. Epub 2021 Nov 8.

Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Purpose: To evaluate aerobic exercise capacity in 5-year intensive care unit (ICU) survivors and to assess the association between severity of organ failure in ICU and exercise capacity up to 5-year follow-up.

Methods: Secondary analysis of the EPaNIC follow-up cohort (NCT00512122) including 433 patients screened with cardiopulmonary exercise testing (CPET) between 1 and 5 years following ICU admission. Exercise capacity in 5-year ICU survivors (N = 361) was referenced to a historic sedentary population and further compared to demographically matched controls (N = 49). In 5-year ICU survivors performing a maximal CPET (respiratory exchange ratio > 1.05, N = 313), abnormal exercise capacity was defined as peak oxygen consumption (VOpeak) < 85% of predicted peak oxygen consumption (%predVOpeak), based on the historic sedentary population. Exercise liming factors were identified. To study the association between severity of organ failure, quantified as the maximal Sequential Organ Failure Assessment score during ICU-stay (SOFA-max), and exercise capacity as assessed with VOpeak, a linear mixed model was built, adjusting for predefined confounders and including all follow-up CPET studies.

Results: Exercise capacity was abnormal in 118/313 (37.7%) 5-year survivors versus 1/48 (2.1%) controls with a maximal CPET, p < 0.001. Aerobic exercise capacity was lower in 5-year survivors than in controls (VOpeak: 24.0 ± 9.7 ml/min/kg versus 31.7 ± 8.4 ml/min/kg, p < 0.001; %predVOpeak: 94% ± 31% versus 123% ± 25%, p < 0.001). Muscular limitation frequently contributed to impaired exercise capacity at 5-year [71/118 (60.2%)]. SOFA-max independently associated with VOpeak throughout follow-up.

Conclusions: Critical illness survivors often display abnormal aerobic exercise capacity, frequently involving muscular limitation. Severity of organ failure throughout the ICU stay independently associates with these impairments.
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http://dx.doi.org/10.1007/s00134-021-06541-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575347PMC
December 2021

Clinical practices underlie COVID-19 patient respiratory microbiome composition and its interactions with the host.

Nat Commun 2021 10 29;12(1):6243. Epub 2021 Oct 29.

Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven, Belgium.

Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the respiratory microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 respiratory microbiome studies by analyzing the upper (n = 58) and lower (n = 35) respiratory tract microbiome in well-phenotyped COVID-19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling. We find that time in the intensive care unit and type of oxygen support, as well as associated treatments such as antibiotic usage, explain the most variation within the upper respiratory tract microbiome, while SARS-CoV-2 viral load has a reduced impact. Specifically, mechanical ventilation is linked to altered community structure and significant shifts in oral taxa previously associated with COVID-19. Single-cell transcriptomics of the lower respiratory tract of COVID-19 patients identifies specific oral bacteria in physical association with proinflammatory immune cells, which show higher levels of inflammatory markers. Overall, our findings suggest confounders are driving contradictory results in current COVID-19 microbiome studies and careful attention needs to be paid to ICU stay and type of oxygen support, as bacteria favored in these conditions may contribute to the inflammatory phenotypes observed in severe COVID-19 patients.
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http://dx.doi.org/10.1038/s41467-021-26500-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556379PMC
October 2021

Impact of tight glucose control on circulating 3-hydroxybutyrate in critically ill patients.

Crit Care 2021 Oct 25;25(1):373. Epub 2021 Oct 25.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.

Background: Recent evidence suggests a potentially protective effect of increasing ketone body availability via accepting low macronutrient intake early after onset of critical illness. The impact of blood glucose control with insulin on circulating ketones is unclear. Whereas lowering blood glucose may activate ketogenesis, high insulin concentrations may have the opposite effect. We hypothesized that the previously reported protective effects of tight glucose control in critically ill patients receiving early parenteral nutrition may have been mediated in part by activation of ketogenesis.

Methods: This is a secondary analysis of 3 randomized controlled trials on tight versus liberal blood glucose control in the intensive care unit, including 700 critically ill children and 2748 critically ill adults. All patients received early parenteral nutrition as part of the contemporary standard of care. Before studying a potential mediator role of circulating ketones in improving outcome, we performed a time course analysis to investigate whether tight glucose control significantly affected ketogenesis and to identify a day of maximal effect, if any. We quantified plasma/serum 3-hydroxybutyrate concentrations from intensive care unit admission until day 3 in 2 matched subsets of 100 critically ill children and 100 critically ill adults. Univariable differences between groups were investigated by Kruskal-Wallis test. Differences in 3-hydroxybutyrate concentrations between study days were investigated by Wilcoxon signed-rank test.

Results: In critically ill children and adults receiving early parenteral nutrition, tight glucose control, as compared with liberal glucose control, lowered mean morning blood glucose on days 1-3 (P < 0.0001) via infusing insulin at a higher dose (P < 0.0001). Throughout the study period, caloric intake was not different between groups. In both children and adults, tight glucose control did not affect 3-hydroxybutyrate concentrations, which were suppressed on ICU days 1-3 and significantly lower than the ICU admission values for both groups (P < 0.0001).

Conclusion: Tight versus liberal glucose control in the context of early parenteral nutrition did not affect 3-hydroxybutyrate concentrations in critically ill patients. Hence, the protective effects of tight glucose control in this context cannot be attributed to increased ketone body availability.
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http://dx.doi.org/10.1186/s13054-021-03772-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547101PMC
October 2021

The goal of personalized glucose control in the critically ill remains elusive.

Intensive Care Med 2021 11 17;47(11):1319-1321. Epub 2021 Sep 17.

Department of Cellular and Molecular Medicine, Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1007/s00134-021-06530-yDOI Listing
November 2021

The gut in COVID-19.

Intensive Care Med 2021 09 8;47(9):1024-1027. Epub 2021 Jul 8.

College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1007/s00134-021-06461-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265290PMC
September 2021

Targeted treatment of iron deficiency in prolonged critical illness: an opportunity to improve survival or not?

Crit Care 2021 06 1;25(1):188. Epub 2021 Jun 1.

Clinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

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http://dx.doi.org/10.1186/s13054-021-03590-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170975PMC
June 2021

Kinetics of peripheral blood neutrophils in severe coronavirus disease 2019.

Clin Transl Immunology 2021 29;10(4):e1271. Epub 2021 Apr 29.

Laboratory of Molecular Immunology Department of Microbiology, Immunology and Transplantation Rega Institute, KU Leuven Leuven Belgium.

Objectives: Emerging evidence of dysregulation of the myeloid cell compartment urges investigations on neutrophil characteristics in coronavirus disease 2019 (COVID-19). We isolated neutrophils from the blood of COVID-19 patients receiving general ward care and from patients hospitalised at intensive care units (ICUs) to explore the kinetics of circulating neutrophils and factors important for neutrophil migration and activation.

Methods: Multicolour flow cytometry was exploited for the analysis of neutrophil differentiation and activation markers. Multiplex and ELISA technologies were used for the quantification of protease, protease inhibitor, chemokine and cytokine concentrations in plasma. Neutrophil polarisation responses were evaluated microscopically. Gelatinolytic and metalloproteinase activity in plasma was determined using a fluorogenic substrate. Co-culturing healthy donor neutrophils with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) allowed us to investigate viral replication in neutrophils.

Results: Upon ICU admission, patients displayed high plasma concentrations of granulocyte-colony-stimulating factor (G-CSF) and the chemokine CXCL8, accompanied by emergency myelopoiesis as illustrated by high levels of circulating CD10, immature neutrophils with reduced CXCR2 and C5aR expression. Neutrophil elastase and non-metalloproteinase-derived gelatinolytic activity were increased in plasma from ICU patients. Significantly higher levels of circulating tissue inhibitor of metalloproteinase 1 (TIMP-1) in patients at ICU admission yielded decreased total MMP proteolytic activity in blood. COVID-19 neutrophils were hyper-responsive to CXCL8 and CXCL12 in shape change assays. Finally, SARS-CoV-2 failed to replicate inside human neutrophils.

Conclusion: Our study provides detailed insights into the kinetics of neutrophil phenotype and function in severe COVID-19 patients, and supports the concept of an increased neutrophil activation state in the circulation.
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http://dx.doi.org/10.1002/cti2.1271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082714PMC
April 2021

Role of ketones, ketogenic diets and intermittent fasting in ICU.

Curr Opin Crit Care 2021 08;27(4):385-389

Clinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Purpose Of Review: To summarize the clinical evidence for beneficial effects of ketones, ketogenic diets and intermittent fasting in critical illness, and to review potential mechanisms behind such effects.

Recent Findings: Recent evidence demonstrates that activation of a metabolic fasting response may be beneficial to recover from critical insults. Potential protective mechanisms are, among others, activation of ketogenesis and of damage removal by autophagy. Novel feeding strategies, including ketone supplements, ketogenic diets and intermittent fasting regimens, can activate these pathways - at least partially - in critically ill patients. Randomized controlled trials (RCTs) studying these novel feeding strategies as compared with standard care, are scarce and have not shown consistent benefit. Yet, all RCTs were small and underpowered for clinical endpoints. Moreover, in intermittent fasting studies, the duration of the fasting interval may have been too short to develop a sustained metabolic fasting response.

Summary: These findings open perspectives for the further development of fasting-mimicking diets. Ultimately, clinical benefit should be confirmed by RCTs that are adequately powered for clinically relevant, patient-centered endpoints.
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http://dx.doi.org/10.1097/MCC.0000000000000841DOI Listing
August 2021

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization.

Semin Thromb Hemost 2021 Jun 23;47(4):362-371. Epub 2021 Apr 23.

Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.

Background:  Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis.

Methods:  Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation-perfusion (V/Q) scan to screen for incidental pulmonary embolism.

Results:  Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported.

Conclusion:  In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.
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http://dx.doi.org/10.1055/s-0041-1727284DOI Listing
June 2021

Five-year outcome of respiratory muscle weakness at intensive care unit discharge: secondary analysis of a prospective cohort study.

Thorax 2021 06 12;76(6):561-567. Epub 2021 Mar 12.

Cellular and Molecular Medicine, KU Leuven, Leuven, Flanders, Belgium

Purpose: To assess the association between respiratory muscle weakness (RMW) at intensive care unit (ICU) discharge and 5-year mortality and morbidity, independent from confounders including peripheral muscle strength.

Methods: Secondary analysis of the prospective 5-year follow-up of the EPaNIC cohort (ClinicalTrials.gov: NCT00512122), limited to 366 patients screened for respiratory and peripheral muscle strength in the ICU with maximal inspiratory pressure (MIP) after removal of the artificial airway, and the Medical Research Council sum score. RMW was defined as an absolute value of MIP <30 cmHO. Associations between RMW at (or closest to) ICU discharge and all-cause 5-year mortality, and key measures of 5-year physical function, comprising respiratory muscle strength (MIP), hand-grip strength (HGF), 6 min walk distance (6MWD) and physical function of the SF-36 quality-of-life questionnaire (PF-SF-36), were assessed with Cox proportional hazards and linear regression models, adjusted for confounders including peripheral muscle strength.

Results: RMW was present in 136/366 (37.2%) patients at ICU discharge. RMW was not independently associated with 5-year mortality (HR with 95% CI 1.273 (0.751 to 1.943), p=0.352). Among 156five-year survivors, those with, as compared with those without RMW demonstrated worse physical function (MIP (absolute value, cmHO): 62(42-77) vs 94(78-109), p<0.001; HGF (%pred): 67(44-87) vs 96(68-110), p<0.001; 6MWD (%pred): 87(74-102) vs 99 (80-111), p=0.009; PF-SF-36 (score): 55 (30-80) vs 80 (55-95), p<0.001). Associations between RMW and morbidity endpoints remained significant after adjustment for confounders (effect size with 95% CI: MIP: -23.858 (-32.097 to -15.027), p=0.001; HGF: -18.591 (-30.941 to -5.744), p=0.001; 6MWD (transformed): -1587.007 (-3073.763 to -179.253), p=0.034; PF-SF-36 (transformed): 1.176 (0.144-2.270), p=0.036).

Conclusions: RMW at ICU discharge is independently associated with 5-year morbidity but not 5-year mortality.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216720DOI Listing
June 2021

Impact of withholding early parenteral nutrition in adult critically ill patients on ketogenesis in relation to outcome.

Crit Care 2021 03 11;25(1):102. Epub 2021 Mar 11.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.

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http://dx.doi.org/10.1186/s13054-021-03519-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953645PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Are periods of feeding and fasting protective during critical illness?

Curr Opin Clin Nutr Metab Care 2021 03;24(2):183-188

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Purpose Of Review: To review the mechanisms how intermittent feeding regimens could be beneficial in critically ill patients.

Recent Findings: Large randomized controlled trials (RCTs) have failed to demonstrate consistent benefit of early, enhanced nutritional support to critically ill patients, and some trials even found potential harm. Although speculative, the absence of a clear benefit could be explained by the continuous mode of feeding in these trials, since intermittent feeding regimens had health-promoting effects in healthy animals and humans through mechanisms that also appear relevant in critical illness. Potential protective mechanisms include avoidance of the muscle-full effect and improved protein synthesis, improved insulin sensitivity, better preservation of circadian rhythm, and fasting-induced stimulation of autophagy and ketogenesis. RCTs comparing continuous versus intermittent feeding regimens in critically ill patients have shown mixed results, albeit with different design and inclusion of relatively few patients. In all studies, the fasting interval was relatively short (4-6 h maximum), which may be insufficient to develop a full fasting response and associated benefits.

Summary: These findings open perspectives for the design and clinical validation of intermittent feeding regimens for critically ill patients. The optimal mode and duration of the fasting interval, if any, remain unclear.
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http://dx.doi.org/10.1097/MCO.0000000000000718DOI Listing
March 2021

Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages.

Cell Res 2021 03 21;31(3):272-290. Epub 2021 Jan 21.

Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.

How the innate and adaptive host immune system miscommunicate to worsen COVID-19 immunopathology has not been fully elucidated. Here, we perform single-cell deep-immune profiling of bronchoalveolar lavage (BAL) samples from 5 patients with mild and 26 with critical COVID-19 in comparison to BALs from non-COVID-19 pneumonia and normal lung. We use pseudotime inference to build T-cell and monocyte-to-macrophage trajectories and model gene expression changes along them. In mild COVID-19, CD8 resident-memory (T) and CD4 T-helper-17 (T) cells undergo active (presumably antigen-driven) expansion towards the end of the trajectory, and are characterized by good effector functions, while in critical COVID-19 they remain more naïve. Vice versa, CD4 T-cells with T-helper-1 characteristics (T-like) and CD8 T-cells expressing exhaustion markers (T-like) are enriched halfway their trajectories in mild COVID-19, where they also exhibit good effector functions, while in critical COVID-19 they show evidence of inflammation-associated stress at the end of their trajectories. Monocyte-to-macrophage trajectories show that chronic hyperinflammatory monocytes are enriched in critical COVID-19, while alveolar macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, are depleted. In critical COVID-19, monocytes contribute to an ATP-purinergic signaling-inflammasome footprint that could enable COVID-19 associated fibrosis and worsen disease-severity. Finally, viral RNA-tracking reveals infected lung epithelial cells, and a significant proportion of neutrophils and macrophages that are involved in viral clearance.
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http://dx.doi.org/10.1038/s41422-020-00455-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027624PMC
March 2021

Indirect calorimetry: A faithful guide for nutrition therapy, or a fascinating research tool?

Clin Nutr 2021 02 11;40(2):651. Epub 2020 Dec 11.

Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.

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http://dx.doi.org/10.1016/j.clnu.2020.12.007DOI Listing
February 2021

Intermittent Fasting: No Benefit, or Too Fast to Waste?

Chest 2020 12;158(6):2707

Clinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/j.chest.2020.07.071DOI Listing
December 2020

Hypophosphatemia in critically ill adults and children - A systematic review.

Clin Nutr 2021 04 8;40(4):1744-1754. Epub 2020 Oct 8.

Service of Adult Intensive care & Burns, Lausanne University Hospital, Lausanne, Switzerland. Electronic address:

Background & Aims: Phosphate is the main intracellular anion essential for numerous biological processes. Symptoms of hypophosphatemia are non-specific, yet potentially life-threatening. This systematic review process was initiated to gain a global insight into hypophosphatemia, associated morbidity and treatments.

Methods: A systematic review was conducted (PROSPERO CRD42020163191). Nine clinically relevant questions were generated, seven for adult and two for pediatric critically ill patients, and prevalence of hypophosphatemia was assessed in both groups. We identified trials through systematic searches of Medline, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, and Web of Science. Quality assessment was performed using the Cochrane risk of bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies.

Results: For all research questions, we identified 2727 titles in total, assessed 399 full texts, and retained 82 full texts for evidence synthesis, with 20 of them identified for several research questions. Only 3 randomized controlled trials were identified with two of them published only in abstract form, as well as 28 prospective and 31 retrospective studies, and 20 case reports. Relevant risk of bias regarding selection and comparability was identified for most of the studies. No meta-analysis could be performed. The prevalence of hypophosphatemia varied substantially in critically ill adults and children, but no study assessed consecutive admissions to intensive care. In both critically ill adults and children, several studies report that hypophosphatemia is associated with worse outcome (prolonged length of stay and the need for respiratory support, and higher mortality). However, there was insufficient evidence regarding the optimal threshold upon which hypophosphatemia becomes critical and requires treatment. We found no studies regarding the optimal frequency of phosphate measurements, and regarding the time window to correct hypophosphatemia. In adults, nutrient restriction on top of phosphate repletion in patients with refeeding syndrome may improve survival, although evidence is weak.

Conclusions: Evidence on the definition, outcome and treatment of clinically relevant hypophosphatemia in critically ill adults and children is scarce and does not allow answering clinically relevant questions. High quality clinical research is crucial for the development of respective guidelines.
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http://dx.doi.org/10.1016/j.clnu.2020.09.045DOI Listing
April 2021

Continuous Assessment of Gastric Motility and Its Relation to Gastric Emptying in Adult Critically Ill Patients.

JPEN J Parenter Enteral Nutr 2020 Oct 23. Epub 2020 Oct 23.

Department of Cellular and Molecular Medicine, Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium.

Background: Critically ill patients frequently develop feeding intolerance, which is difficult to predict. In healthy subjects, gastric motility, assessed by nasogastric balloon tube, correlated with gastric emptying. We now investigated this correlation in critically ill patients, as well as the feasibility and safety of such application in a pilot study.

Methods: Endotracheally intubated adults scheduled to receive enteral nutrition (EN) were included. After insertion of a double-lumen nasogastric balloon tube and radiographic confirmation of position, balloon pressure was recorded for 10 hours after inflation (4 hours fasted, 2 hours during administration of C-labeled EN, and 4 hours postprandially). Gastric motility was expressed as Gastric Balloon Motility Index (GBMI), reflecting the fraction of time in which phasic gastric contractions occurred. Gastric emptying was assessed by C-octanoate breath test and expressed as gastric half-emptying time (GET½). Correlation between GBMI (assessed in different time intervals) and GET½ was investigated by Pearson/Spearman correlation. Feasibility was defined as the success of tube placement and pressure recording. Safety was assessed based on adverse device effects.

Results: Thirty patients were enrolled, of whom 19 had paired GBMI and GET½ data. There was no correlation between GBMI and GET½. The tube was successfully placed in 28/30 (93.3%) patients. In 3/28 (10.7%) patients, balloon leakage precluded analysis. Two safety events were directly linked to the device.

Conclusion: This pilot study showed no significant correlation between balloon-assessed gastric motility and emptying in critically ill patients. The feasibility/safety profile of the balloon tube appears similar to that of standard nasogastric tubes.
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http://dx.doi.org/10.1002/jpen.2037DOI Listing
October 2020

Propofol-infusion syndrome in traumatic brain injury: consider the ECMO option.

Intensive Care Med 2021 01 14;47(1):127-129. Epub 2020 Oct 14.

Department of Intensive Care Medicine, University Hospitals Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1007/s00134-020-06280-3DOI Listing
January 2021

The clinical potential of GDF15 as a "ready-to-feed indicator" for critically ill adults.

Crit Care 2020 09 14;24(1):557. Epub 2020 Sep 14.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.

Background: Circulating growth-differentiation factor-15 (GDF15), a cellular stress marker, abruptly increases during critical illness, but its later time course remains unclear. GDF15 physiologically controls oral intake by driving aversive responses to nutrition. Early parenteral nutrition (PN) in ICU patients has overall been shown not beneficial. We hypothesized that low GDF15 can identify patients who benefit from early PN, tolerate enteral nutrition (EN), and resume spontaneous oral intake.

Methods: In secondary analyses of the EPaNIC-RCT on timing of PN initiation (early PN versus late PN) and the prospective observational DAS study, we documented the time course of circulating GDF15 in ICU (N = 1128) and 1 week post-ICU (N = 72), compared with healthy subjects (N = 65), and the impact hereon of randomization to early PN versus late PN in propensity score-matched groups (N = 564/group). Interaction between upon-admission GDF15 and randomization for its outcome effects was investigated (N = 4393). Finally, association between GDF15 and EN tolerance in ICU (N = 1383) and oral intake beyond ICU discharge (N = 72) was studied.

Results: GDF15 was elevated throughout ICU stay, similarly in early PN and late PN patients, and remained high beyond ICU discharge (p < 0.0001). Upon-admission GDF15 did not interact with randomization to early PN versus late PN for its outcome effects, but higher GDF15 independently related to worse outcomes (p ≤ 0.002). Lower GDF15 was only weakly related to gastrointestinal tolerance (p < 0.0001) and a steeper drop in GDF15 with more oral intake after ICU discharge (p = 0.05).

Conclusion: In critically ill patients, high GDF15 reflected poor prognosis and may contribute to aversive responses to nutrition. However, the potential of GDF15 as "ready-to-feed indicator" appears limited.

Trial Registration: ClinicalTrials.gov , NCT00512122, registered 31 July 2007, https://www.clinicaltrials.gov/ct2/show/NCT00512122 (EPaNIC trial) and ISRCTN, ISRCTN 98806770, registered 11 November 2014, http://www.isrctn.com/ISRCTN98806770 (DAS trial).
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http://dx.doi.org/10.1186/s13054-020-03254-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488998PMC
September 2020

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit.

Crit Care 2020 08 31;24(1):536. Epub 2020 Aug 31.

Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.

Background: In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits.

Methods: In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators.

Results: In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1-5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04-0.04] mmol/L to 0.75 [0.04-2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN statistically explained its impact on weaning from mechanical ventilation (P = 0.0002) and on time to live PICU discharge (P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings.

Conclusion: Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.
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http://dx.doi.org/10.1186/s13054-020-03256-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456767PMC
August 2020

Monitoring and parenteral administration of micronutrients, phosphate and magnesium in critically ill patients: The VITA-TRACE survey.

Clin Nutr 2021 02 14;40(2):590-599. Epub 2020 Jun 14.

KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Intensive Care Medicine, Leuven, Belgium. Electronic address:

Background & Aims: Despite the presumed importance of preventing and treating micronutrient and mineral deficiencies, it is still not clear how to optimize measurement and administration in critically ill patients. In order to design future comparative trials aimed at optimizing micronutrient and mineral management, an important first step is to gain insight in the current practice of micronutrient, phosphate and magnesium monitoring and administration.

Methods: Within the metabolism-endocrinology-nutrition (MEN) section of the European Society of Intensive Care Medicine (ESICM), the micronutrient working group designed a survey addressing current practice in parenteral micronutrient and mineral administration and monitoring. Invitations were sent by the ESICM research department to all ESICM members and past members.

Results: Three hundred thirty-four respondents completed the survey, predominantly consisting of physicians (321 [96.1%]) and participants working in Europe (262 [78.4%]). Eighty-one (24.3%) respondents reported to monitor micronutrient deficiencies through clinical signs and/or laboratory abnormalities, and 148 (44.3%) reportedly measure blood micronutrient concentrations on a routine basis. Two hundred ninety-two (87.4%) participants provided specific data on parenteral micronutrient supplementation, of whom 150 (51.4%) reported early administration of combined multivitamin and trace element preparations at least in selected patients. Among specific parenteral micronutrient preparations, thiamine (146 [50.0%]) was reported to be the most frequently administered micronutrient, followed by vitamin B complex (104 [35.6%]) and folic acid (86 [29.5%]). One hundred twenty (35.9%) and 113 (33.8%) participants reported to perform daily measurements of phosphate and magnesium, respectively, whereas 173 (59.2%) and 185 (63.4%) reported to routinely supplement these minerals parenterally.

Conclusion: The survey revealed a wide variation in current practices of micronutrient, phosphate and magnesium measurement and parenteral administration, suggesting a risk of insufficient prevention, diagnosis and treatment of deficiencies. These results provide the context for future comparative studies, and identify areas for knowledge translation and recommendations.
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http://dx.doi.org/10.1016/j.clnu.2020.06.005DOI Listing
February 2021

Towards a fasting-mimicking diet for critically ill patients: the pilot randomized crossover ICU-FM-1 study.

Crit Care 2020 05 24;24(1):249. Epub 2020 May 24.

Department of Cellular and Molecular Medicine, Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.

Background: In two recent randomized controlled trials, withholding parenteral nutrition early in critical illness improved outcome as compared to early up-to-calculated-target nutrition, which may be explained by beneficial effects of fasting. Outside critical care, fasting-mimicking diets were found to maintain fasting-induced benefits while avoiding prolonged starvation. It is unclear whether critically ill patients can develop a fasting response after a short-term nutrient interruption. In this randomized crossover pilot study, we investigated whether 12-h nutrient interruption initiates a metabolic fasting response in prolonged critically ill patients. As a secondary objective, we studied the feasibility of monitoring autophagy in blood samples.

Methods: In a single-center study in 70 prolonged critically ill patients, 12-h up-to-calculated-target feeding was alternated with 12-h fasting on day 8 ± 1 in ICU, in random order. Blood samples were obtained at the start of the study, at the crossover point, and at the end of the 24-h study period. Primary endpoints were a fasting-induced increase in serum bilirubin and decrease in insulin requirements to maintain normoglycemia. Secondary outcomes included serum insulin-like growth factor I (IGF-I), serum urea, plasma beta-hydroxybutyrate (BOH), and mRNA and protein markers of autophagy in whole blood and isolated white blood cells. To obtain a healthy reference, mRNA and protein markers of autophagy were assessed in whole blood and isolated white blood cells of 23 matched healthy subjects in fed and fasted conditions. Data were analyzed using repeated-measures ANOVA, Fisher's exact test, or Mann-Whitney U test, as appropriate.

Results: A 12-h nutrient interruption significantly increased serum bilirubin and BOH and decreased insulin requirements and serum IGF-I (all p ≤ 0.001). Urea was not affected. BOH was already increased from 4 h fasting onwards. Autophagic markers in blood samples were largely unaffected by fasting in patients and healthy subjects.

Conclusions: A 12-h nutrient interruption initiated a metabolic fasting response in prolonged critically ill patients, which opens perspectives for the development of a fasting-mimicking diet. Blood samples may not be a good readout of autophagy at the tissue level.

Trial Registration: ISRCTN, ISRCTN98404761. Registered 3 May 2017.
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http://dx.doi.org/10.1186/s13054-020-02987-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245817PMC
May 2020

Gastrointestinal dysfunction in the critically ill: a systematic scoping review and research agenda proposed by the Section of Metabolism, Endocrinology and Nutrition of the European Society of Intensive Care Medicine.

Crit Care 2020 05 15;24(1):224. Epub 2020 May 15.

The University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia.

Background: Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies.

Methods: This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds.

Results: Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness.

Conclusions: Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.
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http://dx.doi.org/10.1186/s13054-020-02889-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226709PMC
May 2020

Five-year impact of ICU-acquired neuromuscular complications: a prospective, observational study.

Intensive Care Med 2020 06 22;46(6):1184-1193. Epub 2020 Jan 22.

Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Purpose: To assess the independent association between ICU-acquired neuromuscular complications and 5-year mortality and morbidity. To explore the optimal threshold of the Medical Research Council (MRC) sum score, assessing weakness, for the prediction of 5-year outcomes.

Methods: Sub-analyses of a prospective, 5-year follow-up study including 883 EPaNIC patients (Early versus Late Parenteral Nutrition in Intensive Care) (Clinicaltrials.gov:NCT00512122), systematically screened in ICU for neuromuscular complications with MRC sum score ('MRC-cohort', N = 600), electrophysiology on day 8 ± 1 to quantify compound muscle action potential ('CMAP-cohort', N = 689), or both ('MRC&CMAP-cohort', N = 415). Associations between ICU-acquired neuromuscular complications and 5-year mortality, hand-grip strength (HGF, %predicted), 6-min-walk distance (6-MWD, %predicted) and physical function of the SF-36 quality-of-life questionnaire (PF-SF-36) at 5-years were assessed with Cox regression and linear regression, adjusted for confounders. The optimal threshold for MRC at ICU discharge to predict 5-year outcomes was determined by martingale residual plots (survival) and scatterplots (morbidity).

Results: Both lower MRC sum score at ICU discharge, indicating less strength [HR, per-point-increase: 0.946 (95% CI 0.928-0.968), p = 0.001], and abnormal CMAP, indicating nerve/muscle dysfunction [HR: 1.568 (95% CI 1.165-2.186), p = 0.004], independently associated with increased 5-year mortality. In the MRC&CMAP-cohort, MRC [HR: 0.956 (95% CI 0.934-0.980), p = 0.001] but not CMAP [HR: 1.478 (95% CI 0.875-2.838), p = 0.088] independently associated with 5-year mortality. Among 205 survivors, low MRC independently associated with low HGF [0.866 (95% CI 0.237-1.527), p = 0.004], low 6-MWD [105.1 (95% CI 12.1-212.9), p = 0.043] and low PF-SF-36 [- 0.119 (95% CI - 0.186 to - 0.057), p = 0.002], whereas abnormal CMAP did not correlate with these morbidity endpoints. Exploratory analyses suggested that MRC ≤ 55 best predicted poor long-term morbidity and mortality. Both MRC ≤ 55 and abnormal CMAP independently associated with 5-year mortality.

Conclusions: ICU-acquired neuromuscular complications may impact 5-year morbidity and mortality. MRC sum score, even if slightly reduced, may affect long-term mortality, strength, functional capacity and physical function, whereas abnormal CMAP only related to long-term mortality.
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http://dx.doi.org/10.1007/s00134-020-05927-5DOI Listing
June 2020

Optimising early nutritional support for medical inpatients.

Lancet 2019 12;394(10214):2069

Clinical Department and Laboratory of Intensive Care Medicine, University Hospitals and Catholic University Leuven, Leuven 3000, Belgium.

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http://dx.doi.org/10.1016/S0140-6736(19)32467-5DOI Listing
December 2019

The urea-creatinine ratio as a novel biomarker of critical illness-associated catabolism.

Intensive Care Med 2019 12 16;45(12):1813-1815. Epub 2019 Oct 16.

Medical Intensive Care Unit, Department of General Internal Medicine and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

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http://dx.doi.org/10.1007/s00134-019-05810-yDOI Listing
December 2019
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