scholarly journals Differential Gene Expression in Circulating CD14+ Monocytes Indicates the Prognosis of Critically Ill Patients with Sepsis

2020 ◽  
Vol 9 (1) ◽  
pp. 127 ◽  
Author(s):  
Anke Liepelt ◽  
Philipp Hohlstein ◽  
Hendrik Gussen ◽  
Jia Xue ◽  
Anna C. Aschenbrenner ◽  
...  

Critical illness and sepsis are characterized by drastic changes in the systemic innate immune response, particularly involving monocytes. The exact monocyte activation profile during sepsis, however, has remained obscure. Therefore, we prospectively analyzed the gene expression profile of circulating CD14+ monocytes from healthy volunteers (n = 54) and intensive care unit (ICU) patients (n = 76), of which n = 36 had sepsis. RNA sequencing of selected samples revealed that monocytes from septic ICU patients display a peculiar activation pattern, which resembles characteristic functional stages of monocyte-derived macrophages and is distinct from controls or non-sepsis ICU patients. Focusing on 55 highly variable genes selected for further investigation, arachidonate 5-lipoxygenase-activating protein (ALOX5AP) was highly upregulated in monocytes of ICU patients and only normalized during 7 days in the ICU in non-sepsis patients. Strikingly, low monocytic guanine nucleotide exchange factor 10-like protein (ARHGEF10L) mRNA expression was associated with the disease severity and mortality of ICU patients. Collectively, our comprehensive analysis of circulating monocytes in critically ill patients revealed a distinct activation pattern, particularly in ICU patients with sepsis. The association with disease severity, the longitudinal recovery or lack thereof during the ICU stay, and the association with prognosis indicate the clinical relevance of monocytic gene expression profiles during sepsis.

Author(s):  
Roberto de la Rica ◽  
Marcio Borges ◽  
María Aranda ◽  
Alberto del Castillo ◽  
Antonia Socias ◽  
...  

ABSTRACTOBJECTIVETo describe the clinical characteristics and epidemiological features of severe (non-ICU) and critically patients (ICU) with COVID-19 at triage, prior hospitalization, in one of the main hospitals in The Balearic Islands health care system.DESIGNRetrospective observational studySETTINGSon Llatzer University Hospital in Palma de Mallorca (Spain)PARTICIPANTSAmong a cohort of 52 hospitalized patients as of 31 March 2020, 48 with complete demographic information and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test, were analyzed. Data were collected between March 15th, 2020, and March 31th 2020, inclusive of these dates.MAIN OUTCOMESClinical, vital signs and routine laboratory outcomes at the time of hospitalization, including symptoms reported prior to hospitalization. Demographics and baseline comorbidities were also collected. Mortality was reported at the end of the study.RESULTS48 patients (27 non-ICU and 21 ICU) resident in Mallorca, Spain (mean age, 66 years, [range, 33-88 years]; 67% males) with positive SARS-CoV-2 infection were analyzed. There were no differences in age or sex among groups (p >.05). Initial symptoms included fever (100%), coughing (85%), dyspnea (76%), diarrhea (42%) and asthenia (21%). The majority of patients in this case series were hospitalized because of low SpO2 (SpO2 below 90%) and presentation of bilateral pneumonia (94%) at triage. ICU patients had a higher prevalence of dyspnea compared to non-ICU patients (95% vs 61%, p = .022). Acute respiratory syndrome (ARDS) was presented in 100% of the ICU-patients. All the patients included in the study required oxygen therapy. ICU-patients had lymphopenia as well as hypoalbuminemia. Inflammatory markers such as lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin were significantly higher in ICU patients compared to non-ICU (p < .001).Lower albumin levels were associated with poor prognosis measured as longer hospital length (r= −0.472, p <.001) and mortality (r= −0.424, p=.003). Interestingly we also found, that MCV was lower among of those patients who died (p=.0002). As of April 28, 2020, 10 patients (8 ICU and 2 non-ICU) had died (21% mortality) and while 100% of the non-ICU patients had been discharged, 33% of ICU patients still remained hospitalized (5 in ICU and 2 had been transferred to ward).CONCLUSIONCritically ill patients with COVID-19 present lymphopenia, hypoalbuminemia as well high levels of inflammation. Lower levels of albumin were associated with poorer outcomes in COVID-19 patients. Albumin might be of importance because of its association with disease severity in patients infected with SARS-CoV-2.WHAT IS ALREADY KNOWN IN THIS TOPICSpain has been hit particularly hard by the pandemic. By the time that this manuscript was written more than 25.000 deaths related to COVID-19 have been confirmed. There is limited information available describing the clinical and epidemiological features of Spanish patients requiring hospitalization for COVID-19. Also, it is important to know the characteristics of the hospitalized patients who become critically illWHAT THIS STUDY ADDSThis small case series provides the first steps towards a comprehensive clinical characterization of severe and critical COVID-19 adult patients in Spain. The overall mortality in our patients was 21%. To our knowledge this is the first report with reporting these features in Spain. At triage the majority of patients had lower SpO2 (<90%) and bilateral pneumonia. The most common comorbidities were hypertension (70%), dyslipidemia (62%) and cardiovascular disease (30%). Critically ill patients present hypoalbuminemia and lymphopenia, as well as higher levels of inflammation. Albumin might be of importance because of its association with disease severity and mortality in patients infected with SARS-CoV-2.


Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 672-681 ◽  
Author(s):  
Damien Chaussabel ◽  
Roshanak Tolouei Semnani ◽  
Mary Ann McDowell ◽  
David Sacks ◽  
Alan Sher ◽  
...  

AbstractMonocyte-derived dendritic cells (DCs) and macrophages (Mϕs) generated in vitro from the same individual blood donors were exposed to 5 different pathogens, and gene expression profiles were assessed by microarray analysis. Responses to Mycobacterium tuberculosis and to phylogenetically distinct protozoan (Leishmania major, Leishmania donovani, Toxoplasma gondii) and helminth (Brugia malayi) parasites were examined, each of which produces chronic infections in humans yet vary considerably in the nature of the immune responses they trigger. In the absence of microbial stimulation, DCs and Mϕs constitutively expressed approximately 4000 genes, 96% of which were shared between the 2 cell types. In contrast, the genes altered transcriptionally in DCs and Mϕs following pathogen exposure were largely cell specific. Profiling of the gene expression data led to the identification of sets of tightly coregulated genes across all experimental conditions tested. A newly devised literature-based clustering algorithm enabled the identification of functionally and transcriptionally homogenous groups of genes. A comparison of the responses induced by the individual pathogens by means of this strategy revealed major differences in the functionally related gene profiles associated with each infectious agent. Although the intracellular pathogens induced responses clearly distinct from the extracellular B malayi, they each displayed a unique pattern of gene expression that would not necessarily be predicted on the basis of their phylogenetic relationship. The association of characteristic functional clusters with each infectious agent is consistent with the concept that antigen-presenting cells have prewired signaling patterns for use in the response to different pathogens.


2021 ◽  
Vol 27 ◽  
Author(s):  
Yuxiang Deng ◽  
Long Yu ◽  
Yujie Zhao ◽  
Jianhong Peng ◽  
Yanbo Xu ◽  
...  

Introduction: Regulator of chromatin condensation 1 (RCC1) is a major guanine-nucleotide exchange factor for Ran GTPase, and it plays key roles in various biological processes. Previous studies have found that RCC1 may play a role in the development of tumors, but little is known about the relationship between RCC1 and colorectal liver oligometastases (CLOs).Methods: One hundred and twenty-nine pairs of matched human CLO samples, including both primary tumor and its liver metastasis specimens, were subjected to immunohistochemistry to determine the location and expression levels of RCC1. Associations between RCC1 and survival as well as gene expression profiling were explored.Results: In this study, we first observed that RCC1 was mildly increased in CLO tumor tissues compared with normal tissues, and the localization was primarily nuclear. In addition, our study found that high RCC1 expression in liver oligometastases was an independent prognostic marker for unfavorable recurrence-free survival and overall survival (p = 0.036 and p = 0.016). Gene expression profiles generated from microarray analysis showed that RCC1 was involved in pathways including “Myc targets,” “E2F targets” and “DNA repair” pathways.Conclusion: Our data indicated that RCC1 was expressed mainly in the nucleus, and strong and significant associations were found between RCC1 expression levels and the survival of CLO patients. These findings indicated that RCC1 may play a role in CLO development.


Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Meint Volbeda ◽  
Daniela Jou-Valencia ◽  
Marius C. van den Heuvel ◽  
Marjolein Knoester ◽  
Peter J. Zwiers ◽  
...  

Abstract Background The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury. Methods This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3–4 days for bacterial sepsis patients. Results We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19. Conclusions In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.


2019 ◽  
Author(s):  
Lu Wang ◽  
Chin-Yi Chu ◽  
Matthew N. McCall ◽  
Christopher Slaunwhite ◽  
Jeanne Holden-Wiltse ◽  
...  

AbstractBackgroundA substantial number of infants infected with RSV develop severe symptoms requiring hospitalization. We currently lack accurate biomarkers that are associated with severe illness.MethodWe defined airway gene expression profiles based on RNA sequencing from nasal brush samples from 106 full-tem previously healthy RSV infected subjects during acute infection (day 1-10 of illness) and convalescence stage (day 28 of illness). All subjects were assigned a clinical illness severity score (GRSS). Using AIC-based model selection, we built a sparse linear correlate of GRSS based on 41 genes (NGSS1). We also built an alternate model based upon 13 genes associated with severe infection acutely but displaying stable expression over time (NGSS2).ResultsNGSS1 is strongly correlated with the disease severity, demonstrating a naïve correlation (ρ) of ρ=0.935 and cross-validated correlation of 0.813. As a binary classifier (mild versus severe), NGSS1 correctly classifies disease severity in 89.6% of the subjects following cross-validation. NGSS2 has slightly less, but comparable, accuracy with a cross-validated correlation of 0.741 and classification accuracy of 84.0%.ConclusionAirway gene expression patterns, obtained following a minimally-invasive procedure, have potential utility for development of clinically useful biomarkers that correlate with disease severity in primary RSV infection.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3571-3571
Author(s):  
Sule Bakanay ◽  
Ferdane Kutlar ◽  
Joshi Ratanmani ◽  
Betsy Clair ◽  
Leigh Wells ◽  
...  

Abstract Chronic inflammation is a well-established feature of sickle cell disease (SCD) even at steady state, and the degree of inflammation tends to correlate with disease severity. Elevated neutrophil count, as a reflection of the overall inflammatory state, has emerged as an indicator of poor prognosis and has been associated with adverse outcomes including stroke and early mortality. To further delineate the role of neutrophils in the pathogenesis of various complications and in overall disease severity in SCD, we analyzed the gene expression profiles of neutrophils from 5 patients with "severe" disease (>3 vaso-occlusive episodes [VOE] per year), 5 patients with "mild" disease (<3 VOE/year) and compared these to each other and to the gene expression profiles of neutrophils from 5 age and sex matched, healthy, non-sickle cell, African-American individuals. Granulocytes were separated from freshly collected venous blood using Histopaque (Sigma diagnostic) density gradient separation. Total RNA was extracted immediately after cell separation by using Rneasy Mini Kit (Qiagen). 2 micrograms of total RNA was converted to double stranded cDNA (ds-cDNA) by using SuperScript Choice System (Invitrogen). In vitro transcription was performed on the ds-cDNA using Enzo RNA transcript labelling kit. After the fragmentation, labeled RNA was hybridized to a set of oligonucleotide arrays (HG U133A, Affymetrix, Santa Clara, CA) and the data was analysed with the Microarray suite 5.0 software (Affymetrix). Out of the differentially expressed genes (314 genes for severe vs. control, 718 genes for mild vs control), those with greater than two fold expression were analysed with the geneMAPP software for localization into biological pathways. In general, a larger number of genes were differentially expressed between "mild" patients vs. control, compared to that between "severe" vs "mild" patients. Genes related to cellular proliferation, growth and maintenance, DNA repair, DNA replication, and cell cycle progression were expressed at significantly higher levels in SCD patients compared to controls. The most impressive finding was the significantly higher expression of genes leading to NFkB activation and inhibition of apoptosis: IAP-1 (increased 6.7 fold and 4.7 fold in mild and severe patients respectively), IkB (decreased 0.14 fold and 0.3 fold), Apaf-1 (decreased 0.4 fold in mild), and c-jun (decreased 0.4 fold in severe); Traf-2 (TNF receptor associated factor-2; increased 3.5 fold and 2 fold); genes in the MAPK signalling pathway: ERK-2 (increased 3.5 fold and 2-fold), MAP2K3 (increased 3.5 fold and 2 fold). These data show that neutrophils in SCD patients are activated with higher expression of genes in the TNF, MAPK, and NFkB pathways consistent with an inflammatory state. Delayed or inhibited apoptosis of neutrophils further maintains this inflammatory state even during the so-called "steady state" of the disease. We conclude that the analyses of gene expression in neutrophils can be a useful tool in identifying pathways and genes that distinguish SCD patients from controls and in differentiating mild and severe phenotypes.


2020 ◽  
Author(s):  
Lu Wang ◽  
Chin-Yi Chu ◽  
Matthew N McCall ◽  
Christopher Slaunwhite ◽  
Jeanne Holden-Wiltse ◽  
...  

Abstract BackgroundA substantial number of infants infected with RSV develop severe symptoms requiring hospitalization. We currently lack accurate biomarkers that are associated with severe illness. MethodWe defined airway gene expression profiles based on RNA sequencing from nasal brush samples from 106 full-tem previously healthy RSV infected subjects during acute infection (day 1-10 of illness) and convalescence stage (day 28 of illness). All subjects were assigned a clinical illness severity score (GRSS). Using AIC-based model selection, we built a sparse linear correlate of GRSS based on 41 genes (NGSS1). We also built an alternate model based upon 13 genes associated with severe infection acutely but displaying stable expression over time (NGSS2). ResultsNGSS1 is strongly correlated with the disease severity, demonstrating a naïve correlation (ρ) of ρ=0.935 and cross-validated correlation of 0.813. As a binary classifier (mild versus severe), NGSS1 correctly classifies disease severity in 89.6% of the subjects following cross-validation. NGSS2 has slightly less, but comparable, accuracy with a cross-validated correlation of 0.741 and classification accuracy of 84.0%. ConclusionAirway gene expression patterns, obtained following a minimally-invasive procedure, have potential utility for development of clinically useful biomarkers that correlate with disease severity in primary RSV infection.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lu Wang ◽  
Chin-Yi Chu ◽  
Matthew N. McCall ◽  
Christopher Slaunwhite ◽  
Jeanne Holden-Wiltse ◽  
...  

Abstract Background A substantial number of infants infected with RSV develop severe symptoms requiring hospitalization. We currently lack accurate biomarkers that are associated with severe illness. Method We defined airway gene expression profiles based on RNA sequencing from nasal brush samples from 106 full-tem previously healthy RSV infected subjects during acute infection (day 1–10 of illness) and convalescence stage (day 28 of illness). All subjects were assigned a clinical illness severity score (GRSS). Using AIC-based model selection, we built a sparse linear correlate of GRSS based on 41 genes (NGSS1). We also built an alternate model based upon 13 genes associated with severe infection acutely but displaying stable expression over time (NGSS2). Results NGSS1 is strongly correlated with the disease severity, demonstrating a naïve correlation (ρ) of ρ = 0.935 and cross-validated correlation of 0.813. As a binary classifier (mild versus severe), NGSS1 correctly classifies disease severity in 89.6% of the subjects following cross-validation. NGSS2 has slightly less, but comparable, accuracy with a cross-validated correlation of 0.741 and classification accuracy of 84.0%. Conclusion Airway gene expression patterns, obtained following a minimally-invasive procedure, have potential utility for development of clinically useful biomarkers that correlate with disease severity in primary RSV infection.


2004 ◽  
Vol 171 (4S) ◽  
pp. 349-350
Author(s):  
Gaelle Fromont ◽  
Michel Vidaud ◽  
Alain Latil ◽  
Guy Vallancien ◽  
Pierre Validire ◽  
...  

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