Association between delay in intensive care unit admission and the host response in patients with community-acquired pneumonia

Liza Pereverzeva, Fabrice Uhel, Hessel Peters Sengers, Olaf L Cremer, Marcus J Schultz, Marc M J Bonten, Brendon P Scicluna, Tom van der Poll, MARS consortium, Liza Pereverzeva, Fabrice Uhel, Hessel Peters Sengers, Olaf L Cremer, Marcus J Schultz, Marc M J Bonten, Brendon P Scicluna, Tom van der Poll, MARS consortium

Abstract

Background: A delay in admission to the intensive care unit (ICU) of patients with community-acquired pneumonia (CAP) has been associated with an increased mortality. Decisions regarding interventions and eligibility for immune modulatory therapy are often made at the time of admission to the ICU. The primary aim of this study was to compare the host immune response measured upon ICU admission in CAP patients admitted immediately from the emergency department (direct ICU admission) with those who were transferred within 72 h after admission to the general ward (delayed ICU admission).

Methods: Sixteen host response biomarkers providing insight in pathophysiological mechanisms implicated in sepsis and blood leukocyte transcriptomes were analysed in patients with CAP upon ICU admission in two tertiary hospitals in the Netherlands.

Results: Of 530 ICU admissions with CAP, 387 (73.0%) were directly admitted and 143 (27.0%) had a delayed admission. Patients with a delayed ICU admission were more often immunocompromised (35.0 versus 21.2%, P = .002) and had more malignancies (23.1 versus 13.4%, P = .011). Shock was more present in patients who were admitted to the ICU directly (46.6 versus 33.6%, P = .010). Delayed ICU admission was not associated with an increased hospital mortality risk (hazard ratio 1.25, 95% CI 0.89-1.78, P = .20). The plasma levels of biomarkers (n = 297) reflecting systemic inflammation, endothelial cell activation and coagulation activation were largely similar between groups, with exception of C-reactive protein, soluble intercellular adhesion molecule-1 and angiopoietin-1, which were more aberrant in delayed admissions compared to direct ICU admissions. Blood leukocyte transcriptomes (n = 132) of patients with a delayed ICU admission showed blunted innate and adaptive immune response signalling when compared with direct ICU admissions, as well as decreased gene expression associated with tissue repair and extracellular matrix remodelling pathways.

Conclusions: Blood leukocytes of CAP patients with delayed ICU admission show evidence of a more immune suppressive phenotype upon ICU admission when compared with blood leukocytes from patients directly transferred to the ICU.

Trial registration: Molecular Diagnosis and Risk Stratification of Sepsis (MARS) project, ClinicalTrials.gov identifier NCT01905033.

Keywords: Delayed admission; Host immune response; Intensive care unit; Pneumonia.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Flowchart of patient inclusion. In 75 admissions multiple exclusion criteria were met. CAP community-acquired pneumonia, ICU intensive care unit
Fig. 2
Fig. 2
Host response plasma biomarkers in patients with community-acquired pneumonia with direct or delayed admission to the intensive care unit. Plasma biomarkers were measured on intensive care unit admission. Data are expressed as box-and-whisker plots depicting the median with the lower and upper quartiles. Upper and lower whiskers are defined as measurements that are within 1.5 times the interquartile range of the lowest and highest quartile. Dotted lines indicate median values obtained in 27 healthy subjects. APTT activated partial thromboplastin time, CRP C-reactive protein, ICAM intercellular adhesion molecule, IL interleukin, MMP matrix metalloproteinase, PT prothrombin time. Values in patients were all significantly different from those in healthy controls. * P < .05 (adjusted for multiple testing with the Benjamini–Hochberg false discovery rate approach)
Fig. 3
Fig. 3
Leukocyte genomic responses in patients with community-acquired pneumonia with direct or delayed admission to the intensive care unit. A Volcano plots illustrating the differences in leukocyte genomic responses (integrating log2-fold changes and multiple-test adjusted probabilities) between patients with direct admission to the ICU for community-acquired pneumonia (CAP) and healthy subjects (left), and patients with delayed admission for CAP and healthy subjects (right). Considering adjusted P < .05, 8712 and 7968 genes were identified as differentially expressed in patients admitted directly of with delay for CAP vs healthy subjects, respectively. Blue dots represent significantly underexpressed genes (adjusted P < .05, fold expression < − 1.2), whereas red dots represent significantly overexpressed genes (adjusted P < .05, fold expression > 1.2) in patients relative to healthy controls. Horizontal dotted line indicates multiple-test adjusted Benjamini–Hochberg (BH) P < .05 threshold. Within plots, pie charts show the extent of gene expression changes: blue slices show significantly underexpressed genes (adjusted P < .05 and expression more than 1.2-times decreased compared with healthy controls), red slices show significantly overexpressed genes (adjusted P < .05 and expression more than 1.2-time increased compared with healthy controls), and grey slices show significantly different gene expression (adjusted P < .05 and expression less than 1.2-time increased or decreased compared with healthy controls). B Venn–-Euler representation of differentially expressed genes on admission in CAP patients with direct or delayed ICU-admission vs healthy subjects (adjusted P < .05). Red arrows denote overexpressed genes, blue arrows denote underexpressed genes. C Dot plot depicting the common response (log2-fold changes) of CAP patients with direct or delayed ICU-admission as compared with healthy subjects. Rho, Spearman’s correlation coefficient. D Volcano plot illustrating the differences in leukocyte genomic responses on admission between patients with delayed compared with direct admission to the ICU for community-acquired pneumonia (CAP). Considering adjusted P < .05, 268 genes were differentially expressed. E Considering Benjamini–Hochberg’s adjusted P < .05, underexpressed genes were analysed for association with canonical signalling pathways by Ingenuity pathway analysis (IPA, www.ingenuity.com). Pathways are stratified by significance, which was gauged by BH-adjusted Fisher exact probability. –log (BH) P, negative log transformed BH-adjusted P value. Within plots, pie charts show the extent of gene expression changes in delayed compared to direct admissions for pneumonia

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