Publications by authors named "Peter Pickkers"

373 Publications

Bacteremia in critically ill immunocompromised patients with acute hypoxic respiratory failure: A post-hoc analysis of a prospective multicenter multinational cohort.

J Crit Care 2021 Apr 16;64:114-119. Epub 2021 Apr 16.

Medical Intensive Care Unit, APHP, Hôpital Saint-Louis, Famirea Study Group, ECSTRA team, and Clinical Epidemiology, UMR 1153, Center of Epidemiology and Biostatistics, Sorbonne Paris Cité, CRESS, INSERM, Paris Diderot Sorbonne University, Paris, France.

Purpose: The characteristics and impact of bacteremia have not been widely investigated in immunocompromised patients with acute respiratory failure (ARF).

Methods: We performed a secondary analysis of a prospective cohort of immunocompromised patients with ARF (EFRAIM study). After exclusion of blood cultures positive for coagulase negative Staphylococci, we compared patients with (n = 236) and without (n = 1127) bacteremia.

Results: The incidence of bacteremia was 17%. Bacterial pneumonia and extra-pulmonary ARDS were the main causes of ARF in bacteremic patients. Bacteremia involved gram negative rods (48%), gram positive cocci (40%) or were polymicrobial (10%). Bacteremic patients had more hematological malignancy, higher SOFA scores and increased organ support within 7 days. Bacteremia was associated with higher crude ICU mortality (40% versus 32%, p = 0.02), but neither hospital (49% versus 44%, p = 0.17) nor 90-day mortality (60% versus 56%, p = 0.25) were different from non-bacteremic patients. After propensity score matching based on baseline characteristics, the difference in ICU mortality lost statistical significance (p = 0.06), including in a sensitivity analysis restricted to patients with pneumonia.

Conclusions: We analyzed a large population of immunocompromised patients with ARF and an incidence of bacteremia of 17%. We could not demonstrate an impact of bacteremia on mortality after adjusting for baseline characteristics.
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http://dx.doi.org/10.1016/j.jcrc.2021.03.014DOI Listing
April 2021

Association Between Incident Delirium Treatment With Haloperidol and Mortality in Critically Ill Adults.

Crit Care Med 2021 Apr 5. Epub 2021 Apr 5.

1 Department of Pharmacy and Health Systems Sciences, Bouve College of Health Sciences, Northeastern University, Boston, MA. 2 Department of Intensive Care, Radboud Institute for Health Science, Radboud University Medical Center, Nijmegen, NL. 3 Department of Health Sciences, Bouve College of Health Sciences, Northeastern University, Boston, MA.

Objectives: Haloperidol is commonly administered in the ICU to reduce the burden of delirium and its related symptoms despite no clear evidence showing haloperidol helps to resolve delirium or improve survival. We evaluated the association between haloperidol, when used to treat incident ICU delirium and its symptoms, and mortality.

Design: Post hoc cohort analysis of a randomized, double-blind, placebo-controlled, delirium prevention trial.

Setting: Fourteen Dutch ICUs between July 2013 and December 2016.

Patients: One-thousand four-hundred ninety-five critically ill adults free from delirium at ICU admission having an expected ICU stay greater than or equal to 2 days.

Interventions: Patients received preventive haloperidol or placebo for up to 28 days until delirium occurrence, death, or ICU discharge. If delirium occurred, treatment with open-label IV haloperidol 2 mg tid (up to 5 mg tid per delirium symptoms) was administered at clinician discretion.

Measurements And Main Results: Patients were evaluated tid for delirium and coma for 28 days. Time-varying Cox hazards models were constructed for 28-day and 90-day mortality, controlling for study-arm, delirium and coma days, age, Acute Physiology and Chronic Health Evaluation-II score, sepsis, mechanical ventilation, and ICU length of stay. Among the 1,495 patients, 542 (36%) developed delirium within 28 days (median [interquartile range] with delirium 4 d [2-7 d]). A total of 477 of 542 (88%) received treatment haloperidol (2.1 mg [1.0-3.8 mg] daily) for 6 days (3-11 d). Each milligram of treatment haloperidol administered daily was associated with decreased mortality at 28 days (hazard ratio, 0.93; 95% CI, 0.91-0.95) and 90 days (hazard ratio, 0.97; 95% CI, 0.96-0.98). Treatment haloperidol administered later in the ICU course was less protective of death. Results were stable by prevention study-arm, predelirium haloperidol exposure, and haloperidol treatment protocol adherence.

Conclusions: Treatment of incident delirium and its symptoms with haloperidol may be associated with a dose-dependent improvement in survival. Future randomized trials need to confirm these results.
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http://dx.doi.org/10.1097/CCM.0000000000004976DOI Listing
April 2021

Human in vivo neuroimaging to detect reprogramming of the cerebral immune response following repeated systemic inflammation.

Brain Behav Immun 2021 Apr 9. Epub 2021 Apr 9.

Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Intensive Care Medicine, Nijmegen, the Netherlands; Radboud University Medical Center, Radboud Center for Infectious Diseases, Nijmegen, the Netherlands.

Despite increasing evidence that immune training within the brain may affect the clinical course of neuropsychiatric diseases, data on cerebral immune tolerance are scarce. This study in healthy volunteers examined the trajectory of the immune response systemically and within the brain following repeated lipopolysaccharide (LPS) challenges. Five young males underwent experimental human endotoxemia (intravenous administration of 2 ng/kg LPS) twice with a 7-day interval. The systemic immune response was assessed by measuring plasma cytokine levels. Four positron emission tomography (PET) examinations, using the translocator protein (TSPO) ligand F-DPA-714, were performed in each participant, to assess brain immune cell activation prior to and 5 hours after both LPS challenges. The first LPS challenge caused a profound systemic inflammatory response and resulted in a 53% [95%CI 36-71%] increase in global cerebral F-DPA-714 binding (p < 0.0001). Six days after the first challenge, F-DPA-714 binding had returned to baseline levels (p = 0.399). While the second LPS challenge resulted in a less pronounced systemic inflammatory response (i.e. 77 ± 14% decrease in IL-6 compared to the first challenge), cerebral inflammation was not attenuated, but decreased below baseline, illustrated by a diffuse reduction of cerebral F-DPA-714 binding (-38% [95%CI -47 to -28%], p < 0.0001). Our findings constitute evidence for in vivo immunological reprogramming in the brain following a second inflammatory insult in healthy volunteers, which could represent a neuroprotective mechanism. These results pave the way for further studies on immunotolerance in the brain in patients with systemic inflammation-induced cerebral dysfunction.
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http://dx.doi.org/10.1016/j.bbi.2021.04.004DOI Listing
April 2021

Increased blood angiotensin converting enzyme 2 activity in critically ill COVID-19 patients.

ERJ Open Res 2021 Jan 15;7(1). Epub 2021 Mar 15.

Dept of Intensive Care Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.

https://bit.ly/2MU1z4z.
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http://dx.doi.org/10.1183/23120541.00848-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848790PMC
January 2021

Late augmented renal clearance in patients with COVID-19 in the intensive care unit. A prospective observational study.

J Crit Care 2021 Mar 8;64:7-9. Epub 2021 Mar 8.

Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jcrc.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938790PMC
March 2021

The association of TSH and thyroid hormones with lymphopenia in bacterial sepsis and COVID-19.

J Clin Endocrinol Metab 2021 Mar 13. Epub 2021 Mar 13.

Department of Internal Medicine, Division of Endocrinology, Radboud University Nijmegen, GA, Nijmegen, the Netherlands.

Context: Lymphopenia is a key feature of immune dysfunction in patients with bacterial sepsis and COVID-19 and associated with poor clinical outcomes, but the cause is largely unknown. Severely ill patients may present with thyroid function abnormalities, so-called non-thyroidal illness syndrome (NTIS), and several studies have linked TSH and the thyroid hormones thyroxine (T4) and triiodothyronine (T3) to homeostatic regulation and function of lymphocyte populations.

Purpose: To test the hypothesis that abnormal thyroid function correlates with lymphopenia in patients with severe infections.

Methods: Retrospective analysis of absolute lymphocyte counts, circulating TSH, T4, free T4 (FT4), T3, albumin and inflammatory biomarkers was performed in two independent hospitalized study populations: bacterial sepsis (n=224) and COVID-19 patients (n=161). A subgroup analysis was performed in patients with severe lymphopenia and normal lymphocyte counts.

Results: Only T3 significantly correlated (rho=0.252) with lymphocyte counts in patients with bacterial sepsis and lower concentrations were found in severe lymphopenic compared to non-lympopenic patients (n=56 per group). Severe lymphopenic COVID-19 patients (n=17) showed significantly lower plasma concentrations of TSH, T4, FT4 and T3 compared to patients without lymphopenia (n=18), and demonstrated significantly increased values of the inflammatory markers interleukin-6, C-reactive protein and ferritin. Remarkably, after one week follow-up, the majority (12/15) of COVID-19 patients showed quantitative recovery of their lymphocyte numbers, while TSH and thyroid hormones remained mainly disturbed.

Conclusion: Abnormal thyroid function correlates with lymphopenia in patients with severe infections, like bacterial sepsis and COVID-19, but future studies need to establish whether a causal relationship is involved.
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http://dx.doi.org/10.1210/clinem/dgab148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989224PMC
March 2021

Lysine methyltransferase G9a is an important modulator of trained immunity.

Clin Transl Immunology 2021 18;10(2):e1253. Epub 2021 Feb 18.

Department of Internal Medicine Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen The Netherlands.

Objectives: Histone methyltransferase G9a, also known as Euchromatic Histone Lysine Methyltransferase 2 (EHMT2), mediates H3K9 methylation which is associated with transcriptional repression. It possesses immunomodulatory effects and is overexpressed in multiple types of cancer. In this study, we investigated the role of G9a in the induction of trained immunity, a innate immune memory, and its effects in non-muscle-invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette-Guérin (BCG).

Methods: EHMT2 expression was assessed upon induction of trained immunity by RNA sequencing and Western blotting. G9a inhibitor BIX-01294 was used to investigate the effect on trained immunity responses . Subsequent cytokine production was measured by ELISA, epigenetic modifications were measured by ChIP-qPCR, Seahorse technology was used to measure metabolic changes, and a luminescence assay was used to measure ROS release. RNA sequencing was performed on BIX-01294-treated monocytes .

Results: The expression of EHMT2 mRNA and protein decreased in monocytes during induction of trained immunity. G9a inhibition by BIX-01294 induced trained immunity and amplified trained immunity responses evoked by various microbial ligands . This was accompanied by decreased H3K9me2 at the promoters of pro-inflammatory genes. G9a inhibition was also associated with amplified trained immunity responses in circulating monocytes of NMIBC patients. Additionally, altered RNA expression of inflammatory genes in monocytes of NMIBC patients was observed upon G9a inhibition. Furthermore, intravesical BCG therapy decreased H3K9me2 at the promoter of pro-inflammatory genes.

Conclusion: Inhibition of G9a is important in the induction of trained immunity, and G9a may represent a novel therapeutic target in NMIBC patients.
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http://dx.doi.org/10.1002/cti2.1253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890679PMC
February 2021

Safety and Efficacy of Human Chorionic Gonadotropin Hormone-Derivative EA-230 in Cardiac Surgery Patients: A Randomized Double-Blind Placebo-Controlled Study.

Crit Care Med 2021 May;49(5):790-803

Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

Objectives: To determine the safety and efficacy of human chorionic gonadotropin hormone-derivative EA-230 in cardiac surgery patients. Cardiac surgery induces systemic inflammation and may impair renal function, affecting patient outcome. EA-230 exerted immunomodulatory and renoprotective effects in preclinical models and was safe and showed efficacy in phase I and II human studies.

Design: Double-blinded, placebo-controlled, randomized study.

Setting: Collaboration of the Cardiothoracic Surgery, Anesthesiology, and the Intensive Care departments of a tertiary hospital in the Netherlands.

Patients: One hundred eighty patients undergoing an on-pump coronary artery bypass procedure with or without concomitant valve surgery.

Interventions: Ninety mg/kg/hr EA-230 or placebo administered during surgery.

Measurements And Main Results: During the study, no safety concerns emerged. EA-230 did not modulate interleukin-6 plasma concentrations (area under the curve 2,730 pg/mL × hr [1,968-3,760] vs 2,680 pg/mL × hr [2,090-3,570] for EA-230 and placebo group, respectively; p = 0.80). Glomerular filtration rate increased following surgery (mean ± sem increase in the EA-230 vs placebo groups: glomerular filtration rateiohexol measured using iohexol plasma clearance: 19 ± 2 vs 16 ± 2 mL/min/1.73 m2; p = 0.13 and estimated glomerular filtration rate with the Modification of Diet in Renal Disease equation using creatinine: 6 ± 1 vs 2 ± 1 mL/min/1.73 m2; p = 0.01). The "injury" stage of the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease criteria for acute kidney injury was 7% in the EA-230 group versus 18% in the placebo group (p = 0.07). In addition, EA-230-treated patients had a less positive fluid balance compared with placebo-treated patients (217 ± 108 vs 605 ± 103 mL; p = 0.01), while the use of vasoactive agents was similar in both groups (p = 0.39). Finally, hospital length of stay was shorter in EA-230 treated patients (8 d [7-11] vs 10 d [8-12]; p = 0.001). Efficacy results were more pronounced in patients that had longer duration of surgery and thus longer duration of study drug infusion.

Conclusions: EA-230 was safe in patients undergoing on-pump cardiac surgery. It did not modulate interleukin-6 plasma concentrations but appeared to exert beneficial renal and cardiovascular effects and shortened in-hospital length of stay.
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http://dx.doi.org/10.1097/CCM.0000000000004847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043513PMC
May 2021

Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study.

Crit Care 2021 02 15;25(1):61. Epub 2021 Feb 15.

Department of Anesthesiology, Critical Care and Burn Center, Lariboisière - Saint-Louis Hospitals, DMU Parabol, AP-HP Nord, University of Paris, Paris, France.

Background: Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of circulating DPP3 (cDPP3) indicate a high risk of organ dysfunction and mortality in cardiogenic shock patients.

Methods: The aim was to assess relationships between cDPP3 during the initial intensive care unit (ICU) stay and short-term outcome in the AdrenOSS-1, a prospective observational multinational study in twenty-four ICU centers in five countries. AdrenOSS-1 included 585 patients admitted to the ICU with severe sepsis or septic shock. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by the Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use and need for renal replacement therapy. cDPP3 levels were measured upon admission and 24 h later.

Results: Median [IQR] cDPP3 concentration upon admission was 26.5 [16.2-40.4] ng/mL. Initial SOFA score was 7 [5-10], and 28-day mortality was 22%. We found marked associations between cDPP3 upon ICU admission and 28-day mortality (unadjusted standardized HR 1.8 [CI 1.6-2.1]; adjusted HR 1.5 [CI 1.3-1.8]) and between cDPP3 levels and change in renal and liver SOFA score (p = 0.0077 and 0.0009, respectively). The higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission; the longer the need for vasopressor(s), mechanical ventilation or RRT and the higher the need for fluid load (all p < 0.005). In patients with cDPP3 > 40.4 ng/mL upon admission, a decrease in cDPP3 below 40.4 ng/mL after 24 h was associated with an improvement of organ function at 48 h and better 28-day outcome. By contrast, persistently elevated cDPP3 at 24 h was associated with worsening organ function and high 28-day mortality.

Conclusions: Admission levels and rapid changes in cDPP3 predict outcome during sepsis. Trial Registration ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.
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http://dx.doi.org/10.1186/s13054-021-03471-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885215PMC
February 2021

Dysregulated innate and adaptive immune responses discriminate disease severity in COVID-19.

J Infect Dis 2021 Feb 1. Epub 2021 Feb 1.

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, The Netherlands.

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive pro-inflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis reveals no specific inflammatory endotypes in COVID-19 patients. Functional assays reveal abrogated adaptive cytokine production (interferon-gamma, interleukin-17 and interleukin-22) and prominent T cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlight potential biomarkers of disease severity.
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http://dx.doi.org/10.1093/infdis/jiab065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928798PMC
February 2021

A higher BMI is not associated with a different immune response and disease course in critically ill COVID-19 patients.

Int J Obes (Lond) 2021 03 25;45(3):687-694. Epub 2021 Jan 25.

Department of Intensive Care Medicine, Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.

Background/objectives: Obesity appears to be an independent risk factor for ICU admission and a severe disease course in COVID-19 patients. An aberrant inflammatory response and impaired respiratory function have been suggested as underlying mechanisms. We investigated whether obesity is associated with differences in inflammatory, respiratory, and clinical outcome parameters in critically ill COVID-19 patients.

Subjects/methods: Sixty-seven COVID-19 ICU patients were divided into obese (BMI ≥ 30 kg/m, n = 18, 72% class I obesity, 28% class II obesity) and non-obese (BMI < 30 kg/m, n = 49) groups. Concentrations of circulating interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, and IL-1 receptor antagonist (RA) were determined from ICU admission until 10 days afterward, and routine laboratory and clinical parameters were collected.

Results: BMI was 32.6 [31.2-34.5] and 26.0 [24.4-27.7] kg/m in the obese and non-obese group, respectively. Apart from temperature, which was significantly lower in obese patients (38.1 [36.9-38.9] vs. 38.7 [38.0 -39.5] °C, p = 0.02), there were no between-group differences on ICU admission. Plasma cytokine concentrations declined over time (p < 0.05 for all), but no differences between obese and non-obese patients were observed. Also, BMI did not correlate with the cytokine response (IL-6 r = 0.09, p = 0.61, TNF-α r = 0.03, p = 0.99, IP-10 r = 0.28, p = 0.11). The kinetics of clinical inflammatory parameters and respiratory mechanics were also similar in both groups. Finally, no differences in time on ventilator, ICU length of stay or 40-day mortality between obese and non-obese patients were apparent.

Conclusions: In COVID-19 patients requiring mechanical ventilation in the ICU, a higher BMI is not related to a different immunological response, unfavorable respiratory mechanics, or impaired outcome.
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http://dx.doi.org/10.1038/s41366-021-00747-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829495PMC
March 2021

Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study.

Br J Anaesth 2021 Mar 20;126(3):652-664. Epub 2021 Jan 20.

Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

Background: Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the β-adrenergic receptor. Phenylephrine, generally regarded as a selective α-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through β-adrenergic affinity.

Methods: Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and α- and β-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30-50 μg kg min i.v.) or saline via micro-osmotic pumps, before LPS administration (5 mg kg i.v.) or caecal ligation and puncture (CLP). Twenty healthy males were randomised to a 5 h infusion of phenylephrine (0.5 μg kg min) or saline before receiving LPS (2 ng kg i.v.).

Results: In vitro, phenylephrine enhanced LPS-induced production of the anti-inflammatory cytokine interleukin (IL)-10 (maximum augmentation of 93%) while attenuating the release of pro-inflammatory mediators. These effects were reversed by pre-incubation with β-antagonists, but not α-antagonists. Plasma IL-10 levels were higher in LPS-challenged mice infused with phenylephrine, whereas pro-inflammatory mediators were reduced. Phenylephrine infusion increased bacterial counts after CLP in peritoneal fluid (+42%, P=0.0069), spleen (+59%, P=0.04), and liver (+35%, P=0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (+76%, P=0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (-15%, P=0.03).

Conclusions: Phenylephrine exerts potent anti-inflammatory effects, possibly involving the β-adrenoreceptor. Phenylephrine promotes bacterial outgrowth after surgical peritonitis. Phenylephrine may therefore compromise host defence in surgical patients and increase susceptibility towards infection.

Clinical Trial Registration: NCT02675868 (Clinicaltrials.gov).
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http://dx.doi.org/10.1016/j.bja.2020.11.040DOI Listing
March 2021

Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients.

Genome Med 2021 01 13;13(1). Epub 2021 Jan 13.

Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Background: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system.

Methods: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings.

Results: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.

Conclusions: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.
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http://dx.doi.org/10.1186/s13073-020-00823-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805430PMC
January 2021

Anakinra treatment in critically ill COVID-19 patients: a prospective cohort study.

Crit Care 2020 12 10;24(1):688. Epub 2020 Dec 10.

Department of Intensive Care Medicine, Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.

Background: A subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation.

Methods: In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day - 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment.

Results: Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) (p = 0.0002), ferritin (p = 0.009), and temperature (p = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature (p = 0.03), white blood cell counts (p = 0.02), and plasma levels of ferritin (p = 0.003), procalcitonin (p = 0.001), creatinine (p = 0.01), and bilirubin (p = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results.

Conclusions: Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.
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http://dx.doi.org/10.1186/s13054-020-03364-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726611PMC
December 2020

Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19.

Immunity 2020 12 26;53(6):1296-1314.e9. Epub 2020 Nov 26.

Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, 24105 Kiel, Germany. Electronic address:

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.
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http://dx.doi.org/10.1016/j.immuni.2020.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689306PMC
December 2020

A mould infection in disguise.

Clin Microbiol Infect 2020 Nov 27. Epub 2020 Nov 27.

Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, the Netherlands; Center of Expertise in Mycology Radboudumc/CWZ, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.cmi.2020.11.020DOI Listing
November 2020

Endotoxemia-Induced Release of Pro-inflammatory Mediators Are Associated With Increased Glomerular Filtration Rate in Humans .

Front Med (Lausanne) 2020 5;7:559671. Epub 2020 Nov 5.

Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands.

Sepsis is the most prevalent cause of Acute Kidney Injury (AKI). Conversely, in some septic patients the glomerular filtration rate (GFR) is augmented. The role of the inflammatory response and blood pressure to induce this increased GFR is unknown. Herein, we relate inflammatory mediators and blood pressure to the iohexol clearance-derived "true" GFR and kidney injury markers during systemic inflammation in healthy volunteers. Twelve healthy subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli-derived lipopolysaccharide, LPS). As a gold-standard to determine the GFR, iohexol plasma clearance (GFR) was calculated during a 6-h period on the day before (baseline) as well as 2 and 24 h after LPS administration. Intra-arterial blood pressure was recorded continuously using a radial artery catheter. Circulating inflammatory mediators and urinary excretion of kidney injury markers were serially measured. Experimental endotoxemia profoundly increased plasma concentrations of inflammatory mediators, including [mean ± SD or median [IQR] peak values (pg/mL) of tumor necrosis factor (TNF)-α: 92 ± 40, interleukin (IL)-6: 1,246 ± 605, IL-8: 374 ± 120, IL-10: 222 ± 119, IL-1 receptor antagonist (RA): 8,955 ± 2,429, macrophage chemoattractant protein (MCP)-1: 2,885 [2,706 - 3,765], vascular adhesion molecule (VCAM)-1: 296,105 ± 34,822, intercellular adhesion molecule (ICAM)-1: 25,0170 ± 41,764]. Mean arterial pressure decreased with 13 ± 11 mmHg ( < 0.0001). No significant increase in the urinary excretion of tubular injury markers was observed following LPS administration. GFR increased from 97 ± 6 at baseline to 118 ± 10 mL/min/1.73m ( < 0.0001) post-LPS administration and returned to baseline levels at 24 h post-LPS (99 ± 9 mL/min/1.73m). Peak plasma concentrations of IL-6 ( = 0.66, = 0.001) and IL-8 ( = 0.51, = 0.009), MCP-1 ( = 0.38, = 0.03) and VCAM-1 levels ( = 0.37, = 0.04) correlated with the increase in GFR, whereas a trend was observed for TNF-α ( = 0.33, = 0.0509) and IL-1RA ( = 0.28, = 0.08). None of the kidney injury markers or changes in blood pressure were associated with GFR In multiple linear regression analysis, both peak IL-6 ( = 0.002) and IL-8 ( = 0.01) concentrations remained significantly correlated with GFR, without collinearity. Concentrations of pro-inflammatory cytokines, but not blood pressure, are correlated with the endotoxemia-induced increase in GFR in healthy volunteers. These findings may indicate that inflammatory mediators orchestrate the augmented GFR observed in a subgroup of sepsis patients.
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http://dx.doi.org/10.3389/fmed.2020.559671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674961PMC
November 2020

Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence.

Metabolism 2021 02 17;115:154434. Epub 2020 Nov 17.

Department of Intensive Care Medicine, Radboud university medical center, Nijmegen, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2020.154434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671645PMC
February 2021

Delirium After TAVR: Crosspassing the Limit of Resilience.

JACC Cardiovasc Interv 2020 11;13(21):2453-2466

Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Patients who undergo transcatheter aortic valve replacement often are frail and elderly. Delirium is a frequently observed complication, associated with impaired recovery, prolonged hospital stay, and mortality. In different hospital settings, interventions that reduced the incidence of delirium resulted in improved clinical outcome and reduced costs. In that context, prevention, early recognition, and timely interventions could be the next step toward better outcomes of transcatheter aortic valve replacement. This review is focused on awareness and recognition of delirium, including predisposing "vulnerability" factors (such as cognitive impairment and carotid artery disease) and "trigger" factors (such as anesthesia, hemodynamic imbalance, and complications). For prevention and treatment, clinicians should focus on sleep hygiene, orientation, pain management, and early mobilization. In case of delirium, a thorough search and treatment of trigger factors is warranted. Future studies should focus on risk assessment, preventive and therapeutic interventions, and their potential benefit in terms of costs and clinical outcomes.
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http://dx.doi.org/10.1016/j.jcin.2020.07.044DOI Listing
November 2020

Breath-synchronized electrical stimulation of the expiratory muscles in mechanically ventilated patients: a randomized controlled feasibility study and pooled analysis.

Crit Care 2020 10 30;24(1):628. Epub 2020 Oct 30.

Department of Intensive Care Medicine, Amsterdam University Medical Centers, location VUmc, Postbox 7505, 1007 MB, Amsterdam, The Netherlands.

Background: Expiratory muscle weakness leads to difficult ventilator weaning. Maintaining their activity with functional electrical stimulation (FES) may improve outcome. We studied feasibility of breath-synchronized expiratory population muscle FES in a mixed ICU population ("Holland study") and pooled data with our previous work ("Australian study") to estimate potential clinical effects in a larger group.

Methods: Holland: Patients with a contractile response to FES received active or sham expiratory muscle FES (30 min, twice daily, 5 days/week until weaned). Main endpoints were feasibility (e.g., patient recruitment, treatment compliance, stimulation intensity) and safety. Pooled: Data on respiratory muscle thickness and ventilation duration from the Holland and Australian studies were combined (N = 40) in order to estimate potential effect size. Plasma cytokines (day 0, 3) were analyzed to study the effects of FES on systemic inflammation.

Results: Holland: A total of 272 sessions were performed (active/sham: 169/103) in 20 patients (N = active/sham: 10/10) with a total treatment compliance rate of 91.1%. No FES-related serious adverse events were reported. Pooled: On day 3, there was a between-group difference (N = active/sham: 7/12) in total abdominal expiratory muscle thickness favoring the active group [treatment difference (95% confidence interval); 2.25 (0.34, 4.16) mm, P = 0.02] but not on day 5. Plasma cytokine levels indicated that early FES did not induce systemic inflammation. Using a survival analysis approach for the total study population, median ventilation duration and ICU length of stay were 10 versus 52 (P = 0.07), and 12 versus 54 (P = 0.03) days for the active versus sham group. Median ventilation duration of patients that were successfully extubated was 8.5 [5.6-12.2] versus 10.5 [5.3-25.6] days (P = 0.60) for the active (N = 16) versus sham (N = 10) group, and median ICU length of stay was 10.5 [8.0-14.5] versus 14.0 [9.0-19.5] days (P = 0.36) for those active (N = 16) versus sham (N = 8) patients that were extubated and discharged alive from the ICU. During ICU stay, 3/20 patients died in the active group versus 8/20 in the sham group (P = 0.16).

Conclusion: Expiratory muscle FES is feasible in selected ICU patients and might be a promising technique within a respiratory muscle-protective ventilation strategy. The next step is to study the effects on weaning and ventilator liberation outcome.

Trial Registration: ClinicalTrials.gov, ID NCT03453944. Registered 05 March 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03453944 .
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http://dx.doi.org/10.1186/s13054-020-03352-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596623PMC
October 2020

Increased Plasma Heparanase Activity in COVID-19 Patients.

Front Immunol 2020 6;11:575047. Epub 2020 Oct 6.

Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. To test this hypothesis, heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n = 10) and COVID-19 patients (n = 48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity was associated with disease severity including the need for intensive care, lactate dehydrogenase levels, and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.
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http://dx.doi.org/10.3389/fimmu.2020.575047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573491PMC
November 2020

How to ventilate obese patients in the ICU.

Intensive Care Med 2020 12 23;46(12):2423-2435. Epub 2020 Oct 23.

Research Unit: PhyMedExp, INSERM U-1046, CNRS, Anesthesia and Critical Care Department (DAR-B), Saint Eloi, University of Montpellier, 34295, Montpellier, cedex 5, France.

Obesity is an important risk factor for major complications, morbidity and mortality related to intubation procedures and ventilation in the intensive care unit (ICU). The fall in functional residual capacity promotes airway closure and atelectasis formation. This narrative review presents the impact of obesity on the respiratory system and the key points to optimize airway management, noninvasive and invasive mechanical ventilation in ICU patients with obesity. Non-invasive strategies should first optimize body position with reverse Trendelenburg position or sitting position. Noninvasive ventilation (NIV) is considered as the first-line therapy in patients with obesity having a postoperative acute respiratory failure. Positive pressure pre-oxygenation before the intubation procedure is the method of reference. The use of videolaryngoscopy has to be considered by adequately trained intensivists, especially in patients with several risk factors. Regarding mechanical ventilation in patients with and without acute respiratory distress syndrome (ARDS), low tidal volume (6 ml/kg of predicted body weight) and moderate to high positive end-expiratory pressure (PEEP), with careful recruitment maneuver in selected patients, are advised. Prone positioning is a therapeutic choice in severe ARDS patients with obesity. Prophylactic NIV should be considered after extubation to prevent re-intubation. If obesity increases mortality and risk of ICU admission in the overall population, the impact of obesity on ICU mortality is less clear and several confounding factors have to be taken into account regarding the "obesity ICU paradox".
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http://dx.doi.org/10.1007/s00134-020-06286-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582031PMC
December 2020

Acute respiratory failure in immunocompromised patients: outcome and clinical features according to neutropenia status.

Ann Intensive Care 2020 Oct 22;10(1):146. Epub 2020 Oct 22.

Medical Intensive Care Unit, APHP, Hôpital Saint‑Louis, Famirea Study Group, ECSTRA Team and Clinical Epidemiology, UMR 1153, Center of Epidemiology and Biostatistics, Sorbonne Paris Cité, CRESS, INSERM, Paris Diderot Sorbonne University, Paris, France.

Background: The impact of neutropenia in critically ill immunocompromised patients admitted in a context of acute respiratory failure (ARF) remains uncertain. The primary objective was to assess the prognostic impact of neutropenia on outcomes of these patients. Secondary objective was to assess etiology of ARF according to neutropenia.

Methods: We performed a post hoc analysis of a prospective multicenter multinational study from 23 ICUs belonging to the Nine-I network. Between November 2015 and July 2016, all adult immunocompromised patients with ARF admitted to the ICU were included in the study. Adjusted analyses included: (1) a hierarchical model with center as random effect; (2) propensity score (PS) matched cohort; and (3) adjusted analysis in the matched cohort.

Results: Overall, 1481 patients were included in this study of which 165 had neutropenia at ICU admission (11%). ARF etiologies distribution was significantly different between neutropenic and non-neutropenic patients, main etiologies being bacterial pneumonia (48% vs 27% in neutropenic and non-neutropenic patients, respectively). Initial oxygenation strategy was standard supplemental oxygen in 755 patients (51%), high-flow nasal oxygen in 165 (11%), non-invasive ventilation in 202 (14%) and invasive mechanical ventilation in 359 (24%). Before adjustment, hospital mortality was significantly higher in neutropenic patients (54% vs 42%; p = 0.006). After adjustment for confounder and center effect, neutropenia was no longer associated with outcome (OR 1.40, 95% CI 0.93-2.11). Similar results were observed after matching (52% vs 46%, respectively; p = 0.35) and after adjustment in the matched cohort (OR 1.04; 95% CI 0.63-1.72).

Conclusion: Neutropenia at ICU admission is not associated with hospital mortality in this cohort of critically ill immunocompromised patients admitted for ARF. In neutropenic patients, main ARF etiologies are bacterial and fungal infections.
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http://dx.doi.org/10.1186/s13613-020-00764-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581668PMC
October 2020

COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup.

Nat Rev Nephrol 2020 12 15;16(12):747-764. Epub 2020 Oct 15.

Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA, USA.

Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional 'surges' in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI.
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http://dx.doi.org/10.1038/s41581-020-00356-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561246PMC
December 2020

Biomarkers for antimicrobial stewardship: a reappraisal in COVID-19 times?

Crit Care 2020 10 6;24(1):600. Epub 2020 Oct 6.

Department of Intensive Care Medicine, Radboud University Medical Centre, Postbus 9101, 6500 HB, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1186/s13054-020-03291-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538269PMC
October 2020

Recommendations on Acute Kidney Injury Biomarkers From the Acute Disease Quality Initiative Consensus Conference: A Consensus Statement.

JAMA Netw Open 2020 10 1;3(10):e2019209. Epub 2020 Oct 1.

Department of Medicine, University of Padova, Padova, Italy.

Importance: In the last decade, new biomarkers for acute kidney injury (AKI) have been identified and studied in clinical trials. Guidance is needed regarding how best to incorporate them into clinical practice.

Objective: To develop recommendations on AKI biomarkers based on existing data and expert consensus for practicing clinicians and researchers.

Evidence Review: At the 23rd Acute Disease Quality Initiative meeting, a meeting of 23 international experts in critical care, nephrology, and related specialties, the panel focused on 4 broad areas, as follows: (1) AKI risk assessment; (2) AKI prediction and prevention; (3) AKI diagnosis, etiology, and management; and (4) AKI progression and kidney recovery. A literature search revealed more than 65 000 articles published between 1965 and May 2019. In a modified Delphi process, recommendations and consensus statements were developed based on existing data, with 90% agreement among panel members required for final adoption. Recommendations were graded using the Grading of Recommendations, Assessment, Development and Evaluations system.

Findings: The panel developed 11 consensus statements for biomarker use and 14 research recommendations. The key suggestions were that a combination of damage and functional biomarkers, along with clinical information, be used to identify high-risk patient groups, improve the diagnostic accuracy of AKI, improve processes of care, and assist the management of AKI.

Conclusions And Relevance: Current evidence from clinical studies supports the use of new biomarkers in prevention and management of AKI. Substantial gaps in knowledge remain, and more research is necessary.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.19209DOI Listing
October 2020

ICU-acquired pneumonia in immunosuppressed patients with acute hypoxemic respiratory failure: A post-hoc analysis of a prospective international cohort study.

J Crit Care 2020 Sep 29. Epub 2020 Sep 29.

Medical Intensive Care Unit, APHP, Hôpital Saint-Louis, Famirea Study Group, ECSTRA Team, and Clinical Epidemiology, UMR 1153, Center of Epidemiology, France.

Objective: Intensive Care Units (ICU) acquired Pneumonia (ICU-AP) is one of the most frequent nosocomial infections in critically ill patients. Our aim was to determine the effects of having an ICU-AP in immunosuppressed patients with acute hypoxemic respiratory failure.

Design: Post-hoc analysis of a multinational, prospective cohort study in 16 countries.

Settings: ICU.

Patients: Immunosuppressed patients with acute hypoxemic respiratory failure.

Intervention: None.

Measurements And Main Results: The original cohort had 1611 and in this post-hoc analysis a total of 1512 patients with available data on hospital mortality and occurrence of ICU-AP were included. ICU-AP occurred in 158 patients (10.4%). Hospital mortality was higher in patients with ICU-AP (14.8% vs. 7.1% p < 0.001). After adjustment for confounders and centre effect, use of vasopressors (Odds Ratio (OR) 2.22; 95%CI 1.46-3.39) and invasive mechanical ventilation at day 1 (OR 2.12 vs. high flow oxygen; 95%CI 1.07-4.20) were associated with increased risk of ICU-AP while female gender (OR 0.63; 95%CI 0.43-94) and chronic kidney disease (OR 0.43; 95%CI 0.22-0.88) were associated with decreased risk of ICU-AP. After adjustment for confounders and centre effect, ICU-AP was independently associated with mortality (Hazard Ratio 1.48; 95%CI 14.-1.91; P = 0.003).

Conclusions: The attributable mortality of ICU-AP has been repetitively questioned in immunosuppressed patients with acute respiratory failure. This manuscript found that ICU-AP represents an independent risk factor for hospital mortality.
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http://dx.doi.org/10.1016/j.jcrc.2020.09.027DOI Listing
September 2020