scholarly journals Progranulin signaling in sepsis, community-acquired bacterial pneumonia and COVID-19: a comparative, observational study

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Florian Brandes ◽  
Melanie Borrmann ◽  
Dominik Buschmann ◽  
Agnes S. Meidert ◽  
Marlene Reithmair ◽  
...  
Keyword(s):  
Gene Networks ◽  
Diagnostic Performance ◽  
Plasma Concentrations ◽  
Community Acquired Pneumonia ◽  
Molecular Networks ◽  
Toll Like Receptor 4 ◽  
Reactive Protein ◽  
Healthy State ◽  
Registration Number ◽  
Next Generation Sequencing Ngs

Abstract Background Progranulin is a widely expressed pleiotropic growth factor with a central regulatory effect during the early immune response in sepsis. Progranulin signaling has not been systematically studied and compared between sepsis, community-acquired pneumonia (CAP), COVID-19 pneumonia and a sterile systemic inflammatory response (SIRS). We delineated molecular networks of progranulin signaling by next-generation sequencing (NGS), determined progranulin plasma concentrations and quantified the diagnostic performance of progranulin to differentiate between the above-mentioned disorders using the established biomarkers procalcitonin (PCT), interleukin-6 (IL-6) and C-reactive protein (CRP) for comparison. Methods The diagnostic performance of progranulin was operationalized by calculating AUC and ROC statistics for progranulin and established biomarkers in 241 patients with sepsis, 182 patients with SIRS, 53 patients with CAP, 22 patients with COVID-19 pneumonia and 53 healthy volunteers. miRNAs and mRNAs in blood cells from sepsis patients (n = 7) were characterized by NGS and validated by RT-qPCR in an independent cohort (n = 39) to identify canonical gene networks associated with upregulated progranulin at sepsis onset. Results Plasma concentrations of progranulin (ELISA) in patients with sepsis were 57.5 (42.8–84.9, Q25–Q75) ng/ml and significantly higher than in CAP (38.0, 33.5–41.0 ng/ml, p < 0.001), SIRS (29.0, 25.0–35.0 ng/ml, p < 0.001) and the healthy state (28.7, 25.5–31.7 ng/ml, p < 0.001). Patients with COVID-19 had significantly higher progranulin concentrations than patients with CAP (67.6, 56.6–96.0 vs. 38.0, 33.5–41.0 ng/ml, p < 0.001). The diagnostic performance of progranulin for the differentiation between sepsis vs. SIRS (n = 423) was comparable to that of procalcitonin. AUC was 0.90 (95% CI = 0.87–0.93) for progranulin and 0.92 (CI = 0.88–0.96, p = 0.323) for procalcitonin. Progranulin showed high discriminative power to differentiate bacterial CAP from COVID-19 (sensitivity 0.91, specificity 0.94, AUC 0.91 (CI = 0.8–1.0) and performed significantly better than PCT, IL-6 and CRP. NGS and partial RT-qPCR confirmation revealed a transcriptomic network of immune cells with upregulated progranulin and sortilin transcripts as well as toll-like-receptor 4 and tumor-protein 53, regulated by miR-16 and others. Conclusions Progranulin signaling is elevated during the early antimicrobial response in sepsis and differs significantly between sepsis, CAP, COVID-19 and SIRS. This suggests that progranulin may serve as a novel indicator for the differentiation between these disorders. Trial registration: Clinicaltrials.gov registration number NCT03280576 Registered November 19, 2015.

scholarly journals Clinical metagenomics assessments improve diagnosis and outcomes in community-acquired pneumonia

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fei Xie ◽  
Zhimei Duan ◽  
Weiqi Zeng ◽  
Shumei Xie ◽  
Mingzhou Xie ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Clinical Management ◽  
Pathogen Detection ◽  
Community Acquired Pneumonia ◽  
Diagnostic Methods ◽  
Trial Registration ◽  
Clinical Trial Registry ◽  
Registration Number ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background Identifying the causes of community-acquired pneumonia (CAP) is challenging due to the disease’s complex etiology and the limitations of traditional microbiological diagnostic methods. Recent advances in next generation sequencing (NGS)-based metagenomics allow pan-pathogen detection in a single assay, and may have significant advantages over culture-based techniques. Results We conducted a cohort study of 159 CAP patients to assess the diagnostic performance of a clinical metagenomics assay and its impact on clinical management and patient outcomes. When compared to other techniques, clinical metagenomics detected more pathogens in more CAP cases, and identified a substantial number of polymicrobial infections. Moreover, metagenomics results led to changes in or confirmation of clinical management in 35 of 59 cases; these 35 cases also had significantly improved patient outcomes. Conclusions Clinical metagenomics could be a valuable tool for the diagnosis and treatment of CAP. Trial registration Trial registration number with the Chinese Clinical Trial Registry: ChiCTR2100043628.

scholarly journals Decreased plasma phospholipid concentrations and increased acid sphingomyelinase activity are accurate biomarkers for community-acquired pneumonia

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Haroon Arshad ◽  
Juan Carlos López Alfonso ◽  
Raimo Franke ◽  
Katina Michaelis ◽  
Leonardo Araujo ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Plasma Phospholipid ◽  
Organ Damage ◽  
Phospholipid Metabolism ◽  
Community Acquired Pneumonia ◽  
Acid Sphingomyelinase ◽  
Chronic Obstructive ◽  
Target Cells ◽  
Obstructive Pulmonary Disease ◽  
Reactive Protein

Abstract Background There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage. Methods We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls. Results Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphatidylcholines, followed by lysophosphatidylcholines, sphingomyelins and ceramides (three of which were upregulated), and were least in acylcarnitines. Changes in COPD were less pronounced, but also differed qualitatively, e.g. by increases in selected sphingomyelins. We identified highly accurate biomarkers for CAP (AUC ≤ 0.97) and COPD (AUC ≤ 0.93) vs. Controls, and moderately accurate biomarkers for CAP vs. COPD (AUC ≤ 0.83), all of which were phospholipids. Phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins were also markedly decreased in S. aureus-infected human A549 and differentiated THP1 cells. Correlations with C-reactive protein and procalcitonin were predominantly negative but only of mild-to-moderate extent, suggesting that these markers reflect more than merely inflammation. Consistent with the increased ceramide concentrations, increased acid sphingomyelinase activity accurately distinguished CAP (fold change = 2.8, AUC = 0.94) and COPD (1.75, 0.88) from Controls and normalized with clinical resolution. Conclusions The results underscore the high potential of plasma phospholipids as biomarkers for CAP, begin to reveal differences in lipid dysregulation between CAP and infection-associated COPD exacerbation, and suggest that the decreases in plasma concentrations are at least partially determined by changes in host target cells. Furthermore, they provide validation in clinical blood samples of acid sphingomyelinase as a potential treatment target to improve clinical outcome of CAP.

scholarly journals Utility of procalcitonin, C-reactive protein and white blood cells alone and in combination for the prediction of clinical outcomes in community-acquired pneumonia

2015 ◽  
Vol 53 (4) ◽  
Author(s):  
Andriy Zhydkov ◽  
Mirjam Christ-Crain ◽  
Robert Thomann ◽  
Claus Hoess ◽  
Christoph Henzen ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Blood Cells ◽  
White Blood Cells ◽  
Community Acquired Pneumonia ◽  
Adverse Clinical Outcome ◽  
C Reactive Protein ◽  
Prognostic Information ◽  
Reactive Protein

AbstractThe added value of biomarkers, such as procalcitonin (PCT), C-reactive protein (CRP), and white blood cells (WBC), as adjuncts to clinical risk scores for predicting the outcome of patients with community-acquired pneumonia (CAP) is in question. We investigated the prognostic accuracy of initial and follow-up levels of inflammatory biomarkers in predicting death and adverse clinical outcomes in a large and well-defined cohort of CAP patients.We measured PCT, CRP and WBC on days 1, 3, 5, and 7 and followed the patients over 30 days. We applied multivariate regression models and area under the curve (AUC) to investigate associations between these biomarkers, the clinical risk score CURB-65, and clinical outcomes [i.e., death and intensive care unit (ICU) admission].Of 925 patients with CAP, 50 patients died and 118 patients had an adverse clinical outcome. None of the initial biomarker levels significantly improved the CURB-65 score for mortality prediction. Follow-up biomarker levels showed significant independent association with mortality at days 3, 5, and 7 and with improvements in AUC. Initial PCT and CRP levels were independent prognostic predictors of adverse clinical outcome, and levels of all biomarkers during the course of disease provided additional prognostic information.This study provides robust insights into the added prognostic value of inflammatory markers in CAP. Procalcitonin, CRP, and to a lesser degree WBC provided some prognostic information on CAP outcomes, particularly when considering their kinetics at days 5 and 7 and when looking at adverse clinical outcomes instead of mortality alone.

scholarly journals Effects of statins on clinical outcomes in hospitalized patients with community-acquired pneumonia

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052093858
Author(s):  
Rony M. Zeenny ◽  
Hanine Mansour ◽  
Wissam K Kabbara ◽  
Nibal Chamoun ◽  
Myriam Audi ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Length Of Stay ◽  
Hospital Length ◽  
Community Acquired Pneumonia ◽  
Hospital Length Of Stay ◽  
Comorbid Conditions ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Significant Difference ◽  
Chronic Use

Objective We evaluated the effect of chronic use of statins based on C-reactive protein (CRP) levels and hospital length of stay (LOS) in patients admitted with community-acquired pneumonia (CAP). Methods We conducted a retrospective study over 12 months at a teaching hospital in Lebanon comparing patients with CAP taking chronic statins with patients not taking statins. Included patients with CAP were older than age 18 years and had two CRP level measures during hospitalization. CURB-65 criteria were used to assess the severity of pneumonia. A decrease in CRP levels on days 1 and 3, LOS, and normalization of fever were used to assess the response to antibiotics. Results Sixty-one patients were taking statins and 90 patients were not taking statins. Patients on statins had significantly more comorbid conditions; both groups had comparable CURB-65 scores. In both groups, no statistically significant difference was seen for the decrease in CRP level on days 1 and 3 and LOS. No difference in days to normalization of fever was detected in either group. Conclusion No association was found between the chronic use of statins and CRP levels, LOS, or days to fever normalization in patients with CAP.

scholarly journals Inflammatory Biomarker Score Identifies Patients with Six-Fold Increased Risk of One-Year Mortality after Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4599
Author(s):  
Alisa D. Kjaergaard ◽  
Inna M. Chen ◽  
Astrid Z. Johansen ◽  
Børge G. Nordestgaard ◽  
Stig E. Bojesen ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
High Plasma ◽  
Carbohydrate Antigen ◽  
Ductal Adenocarcinoma ◽  
P Value ◽  
Inflammatory Biomarker ◽  
Reactive Protein ◽  
Hazard Ratios ◽  
Increased Risk ◽  
One Year

We examined whether elevated plasma C-reactive protein (CRP), carbohydrate antigen (CA) 19-9, interleukin-6 (IL-6) and YKL-40, individually or combined, can identify poor survivors among patients with pancreatic ductal adenocarcinoma (PDAC). We measured CRP, CA 19-9, IL-6 and YKL-40 in 993 patients at the time of PDAC diagnosis. The biomarker score was the sum of biomarker categories, coded 0, 1 and 2 for low, intermediate and high plasma concentrations, respectively. High vs. low levels of CRP, CA 19-9 and IL-6 were each independently associated with a two-fold increased risk of one-year mortality. CRP performed best in patients with advanced and CA 19-9 in patients with low cancer stages. YKL-40 was not associated with mortality and, therefore, was not included in the biomarker score. Compared to the biomarker score = 0, the multifactorially adjusted hazard ratios for one-year mortality were 1.56 (95% confidence interval: 0.99–2.44) for score = 1, 2.22 (1.41–3.49) for score = 2, 3.44 (2.20–5.38) for score = 3, 5.13 (3.21–8.17) for score = 4 and 6.32 (3.84–10.41) for score = 5–6 (p-value for trend = 3 × 10−31). This score performed better than any single biomarker or combination of biomarkers when examined in similarly sized or other categories. In conclusion, a combination score of elevated CRP, CA 19-9 and IL-6 identified patients with six-fold higher one-year mortality.

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