ABSTRACT
BACKGROUND: HBP, a novel biomarker released from neutrophils, may induce inflammatory responses and exacerbate vascular permeability, representing the pathophysiological characteristics of sepsis and septic shock. However, it remains uncertain whether the combination of HBP with other biomarkers yields enhanced diagnostic capacity for sepsis. We hypothesized that measurements included IL-6·IL-8·HBP, IL-6·IL-8·HBP/ALB and HBP/ALB which based on HBP will improve its diagnostic efficacy and even better than the traditional infection biomarkers. METHODS: Between July 2021 and June 2022, we carried out a comprehensive, multi-center, observational cohort study spanning six leading tertiary hospitals located in Heilongjiang Province, China. Patients were stratified into three categories based on the severity of infection: non-sepsis, sepsis, and septic shock. We collected clinical and laboratory data, along with infection and inflammation biomarkers, for analysis. RESULTS: A total of 195 patients were enrolled. Among the three groups, patients with septic shock (n = 75, 38.5%) had significantly higher baseline levels of HBP, WBC, Lac, CRP, PCT, IL-6, IL-8, and IL-10 compared to non-sepsis patients (n = 43, 22.0%) and sepsis patients (n = 77, 39.5%), with statistically significant differences (p < 0.05) observed for all parameters. When compared to SOFA score and traditional markers of CRP, PCT, IL-6 and IL-8, the combined indexes of IL-6·IL-8·HBP and IL-6·IL-8·HBP/ALB demonstrated significantly improved diagnostic performance for sepsis and septic shock (AUC 0.911 and 0.902 respectively, p < 0.001). CONCLUSIONS: The combined measurements of IL-6·IL-8·HBP and IL-6·IL-8·HBP/ALB can augment the diagnostic capacity of HBP for sepsis, and offer reliable early supplementary indicators to traditional biomarkers for assessing disease severity in patients with infection.
Subject(s)
Biomarkers , Sepsis , Humans , Biomarkers/blood , Female , Male , Middle Aged , Sepsis/diagnosis , Sepsis/blood , Aged , Cohort Studies , China , Blood Proteins/analysis , Interleukin-6/blood , Antimicrobial Cationic Peptides/blood , Shock, Septic/diagnosis , Shock, Septic/blood , Interleukin-8/blood , AdultABSTRACT
OBJECTIVES: This study aims to investigate the diagnostic value of heparin-binding protein (HBP) in sepsis and develop a sepsis diagnostic model incorporating HBP with key biomarkers and disease-related scores for rapid, and accurate diagnosis of sepsis in the intensive care unit (ICU). DESIGN: Clinical retrospective cross-sectional study. SETTING: A comprehensive teaching tertiary hospital in China. PARTICIPANTS: Adult patients (aged ≥18 years) who underwent HBP testing or whose blood samples were collected when admitted to the ICU. MAIN OUTCOME MEASURES: HBP, C reactive protein (CRP), procalcitonin (PCT), white blood cell count (WBC), interleukin-6 (IL-6), lactate (LAC), Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) score were recorded. RESULTS: Between March 2019 and December 2021, 326 patients were enrolled in this study. The patients were categorised into a non-infection group (control group), infection group, sepsis group and septic shock group based on the final diagnosis. The HBP levels in the sepsis group and septic shock group were 45.7 and 69.0 ng/mL, respectively, which were significantly higher than those in the control group (18.0 ng/mL) and infection group (24.0 ng/mL) (p<0.001). The area under the curve (AUC) value of HBP for diagnosing sepsis was 0.733, which was lower than those corresponding to PCT, CRP and SOFA but higher than those of IL-6, LAC and APACHE II. Multivariate logistic regression analysis identified HBP, PCT, CRP, IL-6 and SOFA as valuable indicators for diagnosing sepsis. A sepsis diagnostic model was constructed based on these indicators, with an AUC of 0.901, a sensitivity of 79.7% and a specificity of 86.9%. CONCLUSIONS: HBP could serve as a biomarker for the diagnosis of sepsis in the ICU. Compared with single indicators, the sepsis diagnostic model constructed using HBP, PCT, CRP, IL-6 and SOFA further enhanced the diagnostic performance of sepsis.
Subject(s)
Antimicrobial Cationic Peptides , Biomarkers , Blood Proteins , C-Reactive Protein , Intensive Care Units , Organ Dysfunction Scores , Sepsis , Humans , Retrospective Studies , Cross-Sectional Studies , Female , Male , Biomarkers/blood , Middle Aged , Sepsis/diagnosis , Sepsis/blood , China , Aged , Blood Proteins/analysis , C-Reactive Protein/analysis , C-Reactive Protein/metabolism , Antimicrobial Cationic Peptides/blood , Procalcitonin/blood , APACHE , Interleukin-6/blood , Adult , ROC Curve , Lactic Acid/bloodABSTRACT
BACKGROUND: Sepsis remains a leading cause of death worldwide. In this context, heparin-binding protein (HBP) has emerged as a possible biomarker, drawing significant attention for its diagnostic and prognostic usefulness in septic patients. Despite this advancement, the literature yields conflicting results. This study is intended to critically evaluate the diagnostic and prognostic value of HBP in critically ill septic patients. METHODS: We searched multiple databases, including PubMed, SCOPUS, Web of Science, and EBSCO, to identify relevant studies on April 27, 2023. We included studies investigating sepsis or its severe outcomes that reported HBP levels and the required data to create 2â ×â 2 tables. We used R version 4.2.2 and R Studio to analyze the pooled diagnostic accuracy outcomes. The diagmeta package was utilized to calculate the optimum cutoff value. RESULTS: In our meta-analysis, we incorporated 28 studies including 5508 patients. The analysis revealed that HBP has a sensitivity of 0.71 (95% CI: 0.60; 0.79) and a specificity of 0.68 (95% CI: 0.51; 0.81) in diagnosing sepsis, respectively. HBP demonstrated moderate prognostic accuracy for mortality at a cutoff value of 161.415 ng/mL, with a sensitivity and specificity of 72%, and for severe sepsis outcomes at a cutoff value of 58.907 ng/mL, with a sensitivity and specificity of 71%. CONCLUSION: Our findings indicate a relatively moderate diagnostic and prognostic accuracy of HBP for sepsis. Future studies are required to verify the accuracy of HBP as a biomarker for sepsis.
Subject(s)
Biomarkers , Blood Proteins , Sepsis , Humans , Sepsis/diagnosis , Sepsis/mortality , Sepsis/blood , Prognosis , Biomarkers/blood , Blood Proteins/analysis , Antimicrobial Cationic Peptides/blood , Sensitivity and Specificity , Critical Illness/mortality , Pore Forming Cytotoxic ProteinsABSTRACT
Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) has become the leading cause of chronic liver disease. Liver biopsy, as the diagnostic gold standard, is invasive and has sampling bias, making it particularly important to search for sensitive and specific biomarkers for diagnosis. Cytokeratin 18 (CK18) M30 and M65 are products of liver cell apoptosis and necrosis, respectively, and liver-expressed antimicrobial peptide 2 (LEAP-2) is a related indicator of glucose and lipid metabolism. Correlation studies have found that all three indicators positively correlate with the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Through comparison of diagnostic values, it was found that CK18 M65 can better distinguish between healthy individuals and MAFLD; LEAP-2 can effectively distinguish MAFLD from other liver diseases, especially ALD.
Subject(s)
Antimicrobial Cationic Peptides , Biomarkers , Keratin-18 , Adult , Female , Humans , Male , Middle Aged , Alanine Transaminase/blood , Antimicrobial Cationic Peptides/blood , Aspartate Aminotransferases/blood , Biomarkers/blood , Biopsy , Fatty Liver/diagnosis , Fatty Liver/pathology , Fatty Liver/blood , Keratin-18/blood , Liver/pathology , Peptide Fragments , Sensitivity and SpecificityABSTRACT
The human cathelicidin hCAP-18 (pro-LL-37) is the pro-protein of the antimicrobial peptide LL-37. hCAP-18 can be produced by many different cell types; bone marrow neutrophil precursors are the main source of hCAP-18 in the circulation. Neutrophil count is used as a marker for myelopoiesis but does not always reflect neutrophil production in the bone marrow, and thus additional markers are needed. In this study, we established the reference interval of serum hCAP-18 level in healthy children and compared serum hCAP-18 levels between different diagnostic groups of children with haemato-oncological diseases, at diagnosis. We found that children with diseases that impair myelopoiesis, such as acute leukaemia, aplastic anaemia, or myelodysplastic syndrome, presented with low hCAP-18 levels, whereas patients with non-haematological malignancies displayed serum hCAP-18 levels in the same range as healthy children. Children with chronic myeloid leukaemia presented with high circulating levels of hCAP-18, probably reflecting the high number of all differentiation stages of myeloid cells. We suggest that analysis of serum hCAP-18 provides additional information regarding myelopoiesis in children with haemato-oncological diseases, which may have future implications in assessment of myelopoiesis in clinical management.
Subject(s)
Antimicrobial Cationic Peptides , Hematologic Neoplasms , Neutrophils , Antimicrobial Cationic Peptides/blood , Cell Differentiation , Child , Humans , Leukocyte Count , Neutrophils/metabolism , CathelicidinsABSTRACT
Vitamin D deficiency, characterized by low circulating levels of calcifediol (25-hydroxyvitamin D, 25D) has been linked to increased risk of infections of bacterial and viral origin. Innate immune cells produce hormonal calcitriol (1,25-dihydroxyvitamin D, 1,25D) locally from circulating calcifediol in response to pathogen threat and an immune-specific cytokine network. Calcitriol regulates gene expression through its binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. The hormone-bound VDR induces the transcription of genes integral to innate immunity including pattern recognition receptors, cytokines, and most importantly antimicrobial peptides (AMPs). Transcription of the human AMP genes ß-defensin 2/defensin-ß4 (HBD2/DEFB4) and cathelicidin antimicrobial peptide (CAMP) is stimulated by the VDR bound to promoter-proximal vitamin D response elements. HDB2/DEFB4 and the active form of CAMP, the peptide LL-37, which form amphipathic secondary structures, were initially characterized for their antibacterial actively. Notably, calcitriol signaling induces secretion of antibacterial activity in vitro and in vivo, and low circulating levels of calcifediol are associated with diverse indications characterized by impaired antibacterial immunity such as dental caries and urinary tract infections. However, recent work has also provided evidence that the same AMPs are components of 1,25D-induced antiviral responses, including those against the etiological agent of the COVID-19 pandemic, the SARS-CoV2 coronavirus. This review surveys the evidence for 1,25D-induced antimicrobial activity in vitro and in vivo in humans and presents our current understanding of the potential mechanisms by which CAMP and HBD2/DEFB4 contribute to antiviral immunity.
Subject(s)
Antimicrobial Peptides/immunology , Antiviral Agents/immunology , COVID-19/immunology , Immunity, Innate/immunology , SARS-CoV-2/immunology , Vitamin D/analogs & derivatives , Antimicrobial Cationic Peptides/blood , Antimicrobial Cationic Peptides/immunology , Antimicrobial Peptides/blood , Calcitriol/blood , Calcitriol/immunology , Cathelicidins/blood , Cathelicidins/immunology , Humans , Receptors, Calcitriol/blood , Receptors, Calcitriol/immunology , Signal Transduction/immunology , Vitamin D/blood , Vitamin D/immunology , Vitamin D Deficiency/immunology , Vitamin D Deficiency/virology , beta-Defensins/blood , beta-Defensins/immunologyABSTRACT
Bactericidal/permeability-increasing protein (BPI) exhibits a number of important characteristics. RNA-seq analysis revealed that the BPI expression was increased in platelets of (non)ST-elevated myocardial infarction (NSTEMI/STEMI) patients. Activated platelets can induce NETosis which may be accompanied by the release of myeloperoxidase-DNA (MPO-DNA) and S100A8/A9. This study investigated the plasma BPI levels in myocardial infarction patients and its correlation with MPO-DNA and S100A8/A9. This prospective study recruited 80 control individuals, as well as 63 NSTEMI and 59 STEMI patients who were admitted to the First Affiliated Hospital of Bengbu Medical College for coronary angiography (CAG) and/or percutaneous coronary intervention (PCI) between May 1, 2020 and August 31, 2020. Demographic and clinical characteristics, clinical indicators, hs-CRP, IL-1ß, MPO-DNA (a circulated marker of NETs), circulating levels of S100A8/A9 and BPI were measured from each individual. The severity of coronary lesions was evaluated by the Gensini score, based on the results of the CAG. Pearson's or spearman's correlation was used to examine the correlation between BPI and the above-mentioned parameters, as well as the severity of coronary artery disease. Linear regression analysis was applied to identify the independent predictive factors of BPI. Received operating characteristic (ROC) curve analysis was used to evaluate the diagnostic efficacy of plasma BPI for MI. The plasma BPI levels increased by 8.76 times in the STEMI group and 5.38 times in the NSTEMI group compared to the control group. The plasma level of hs-CRP and IL-1ß in both STEMI and NSTEMI groups were also significantly higher than the control group. In addition, the plasma levels of MPO-DNA and S100A8/A9 in the STEMI and NSTEMI groups were significantly higher than the control group. Plasma levels of BPI were positively correlated with IL-1ß, hs-CRP, MPO-DNA and S100A8/A9. The correlation between BPI and the severity of coronary artery disease was also significant. The optimal cutoff value of plasma BPI was 35.1705 ng/ml for MI patients from the ROC curve analysis. Plasma BPI levels are increased in myocardial infarction patients and positively correlated with MPO-DNA and S100A8/A9. Plasma BPI level may serve as a potential biomarker of myocardial infarction.
Subject(s)
Antimicrobial Cationic Peptides/blood , Coronary Artery Disease , Myocardial Infarction , Non-ST Elevated Myocardial Infarction , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Blood Proteins , C-Reactive Protein , DNA , Humans , Myocardial Infarction/diagnosis , Peroxidase , Prospective Studies , ST Elevation Myocardial Infarction/diagnosisABSTRACT
BACKGROUND: We aimed to establish an acute treatment protocol to increase serum vitamin D, evaluate the effectiveness of vitamin D3 supplementation, and reveal the potential mechanisms in COVID-19. METHODS: We retrospectively analyzed the data of 867 COVID-19 cases. Then, a prospective study was conducted, including 23 healthy individuals and 210 cases. A total of 163 cases had vitamin D supplementation, and 95 were followed for 14 days. Clinical outcomes, routine blood biomarkers, serum levels of vitamin D metabolism, and action mechanism-related parameters were evaluated. RESULTS: Our treatment protocol increased the serum 25OHD levels significantly to above 30 ng/mL within two weeks. COVID-19 cases (no comorbidities, no vitamin D treatment, 25OHD <30 ng/mL) had 1.9-fold increased risk of having hospitalization longer than 8 days compared with the cases with comorbidities and vitamin D treatment. Having vitamin D treatment decreased the mortality rate by 2.14 times. The correlation analysis of specific serum biomarkers with 25OHD indicated that the vitamin D action in COVID-19 might involve regulation of INOS1, IL1B, IFNg, cathelicidin-LL37, and ICAM1. CONCLUSIONS: Vitamin D treatment shortened hospital stay and decreased mortality in COVID-19 cases, even in the existence of comorbidities. Vitamin D supplementation is effective on various target parameters; therefore, it is essential for COVID-19 treatment.
Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Vitamin D/administration & dosage , Antimicrobial Cationic Peptides/blood , Antimicrobial Cationic Peptides/genetics , Antimicrobial Cationic Peptides/metabolism , COVID-19/complications , COVID-19/mortality , Dietary Supplements , Gene Expression Regulation/drug effects , Humans , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interferon-gamma/blood , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-1beta/blood , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Nitric Oxide Synthase Type II/blood , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Prospective Studies , Retrospective Studies , Vitamin D/blood , Vitamin D/pharmacology , Vitamins/administration & dosage , Vitamins/pharmacology , CathelicidinsABSTRACT
The coronavirus disease 2019 (COVID-19) is related to enhanced production of NETs, and autoimmune/autoinflammatory phenomena. We evaluated the proportion of low-density granulocytes (LDG) by flow cytometry, and their capacity to produce NETs was compared with that of conventional neutrophils. NETs and their protein cargo were quantified by confocal microscopy and ELISA. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and the degradation capacity of NETs were addressed in serum. MILLIPLEX assay was used to assess the cytokine levels in macrophages' supernatant and serum. We found a higher proportion of LDG in severe and critical COVID-19 which correlated with severity and inflammatory markers. Severe/critical COVID-19 patients had higher plasmatic NE, LL-37 and HMGB1-DNA complexes, whilst ISG-15-DNA complexes were lower in severe patients. Sera from severe/critical COVID-19 patients had lower degradation capacity of NETs, which was reverted after adding hrDNase. Anti-NET antibodies were found in COVID-19, which correlated with ANA and ANCA positivity. NET stimuli enhanced the secretion of cytokines in macrophages. This study unveils the role of COVID-19 NETs as inducers of pro-inflammatory and autoimmune responses. The deficient degradation capacity of NETs may contribute to the accumulation of these structures and anti-NET antibodies are related to the presence of autoantibodies.
Subject(s)
Autoimmunity , COVID-19/blood , COVID-19/immunology , Extracellular Traps/immunology , Immunity, Humoral , Inflammation , Neutrophils/immunology , Antibodies, Antinuclear , Antimicrobial Cationic Peptides/blood , Autoantibodies/metabolism , Cross-Sectional Studies , Cytokines/metabolism , Cytokines/pharmacology , Flow Cytometry , Granulocytes/metabolism , HMGB1 Protein/blood , Healthy Volunteers , Humans , Microscopy, Confocal , Monocytes/cytology , Neutrophils/cytology , SARS-CoV-2 , Ubiquitins/pharmacology , CathelicidinsABSTRACT
Urinary tract infections (UTI) during pregnancy are frequently associated with hypertensive disorders, increasing the risk of perinatal morbidity. Calcitriol, vitamin D3's most active metabolite, has been involved in blood pressure regulation and prevention of UTIs, partially through modulating vasoactive peptides and antimicrobial peptides, like cathelicidin. However, nothing is known regarding the interplay between placental calcitriol, cathelicidin, and maternal blood pressure in UTI-complicated pregnancies. Here, we analyzed the correlation between these parameters in pregnant women with UTI and with normal pregnancy (NP). Umbilical venous serum calcitriol and its precursor calcidiol were significantly elevated in UTI. Regardless of newborn's sex, we found strong negative correlations between calcitriol and maternal systolic and diastolic blood pressure in the UTI cohort (p < 0.002). In NP, this relationship was observed only in female-carrying mothers. UTI-female placentas showed higher expression of cathelicidin and CYP27B1, the calcitriol activating-enzyme, compared to male and NP samples. Accordingly, cord-serum calcitriol from UTI-female neonates negatively correlated with maternal bacteriuria. Cathelicidin gene expression positively correlated with gestational age in UTI and with newborn anthropometric parameters. Our results suggest that vitamin D deficiency might predispose to maternal cardiovascular risk and perinatal infections especially in male-carrying pregnancies, probably due to lower placental CYP27B1 and cathelicidin expression.
Subject(s)
Blood Pressure/immunology , Calcitriol/blood , Fetal Blood/metabolism , Pregnancy Complications, Infectious/blood , Urinary Tract Infections/blood , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/blood , Adult , Antimicrobial Cationic Peptides/blood , Female , Gestational Age , Humans , Infant, Newborn , Male , Placenta/metabolism , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/microbiology , Sex Factors , Urinary Tract Infections/immunology , Urinary Tract Infections/microbiology , Vitamin D Deficiency/blood , Vitamin D Deficiency/immunology , Vitamin D Deficiency/microbiology , CathelicidinsABSTRACT
AIM: To establish a highly sensitive time-resolved fluorescence immunoassay of heparin-binding protein (HBP-TRFIA) and evaluate its application value for bacterial or fungal infections in tumor patients. METHODS: Two types of HBP monoclonal specific antibodies against different epitopes of the antigen molecule were used as coating antibodies and Eu3+-labeled antibodies, respectively. The double-antibody sandwich method was used in establishing HBP-TRFIA, and the methodology was evaluated. The established HBP-TRFIA was used in detecting HBP concentration in the plasma samples of healthy individuals, patients with bacterial or fungal infections, and infected or uninfected patients with various types of tumors. RESULTS: The linear range of HBP-TRFIA was (0.11-530 ng/mL). Plasma HBP concentrations detected through HBP-TRFIA were consistent with the results of fluorescence quantitative immunochromatography (ρ = 0.964). The plasma HBP concentrations of infected tumor patients were significantly higher than those of uninfected tumor patients (P < 0.01). CONCLUSION: This study successfully established a highly sensitive HBP-TRFIA, which was highly comparable to commercially available fluorescent quantitative immunochromatographic kits and was able to facilitate the timely diagnosis of bacterial or fungal infections in patients with tumor.
Subject(s)
Antimicrobial Cationic Peptides/blood , Antimicrobial Cationic Peptides/immunology , Blood Proteins/immunology , Fluoroimmunoassay/methods , Neoplasms/microbiology , Antibodies, Monoclonal , C-Reactive Protein/analysis , Chromatography, Affinity , Gram-Negative Bacterial Infections/blood , Gram-Positive Bacterial Infections/blood , Humans , Limit of Detection , Mycoses/blood , Neoplasms/blood , Sensitivity and SpecificityABSTRACT
BACKGROUND: Tuberculosis remains a global threat and a public health problem that has eluded attempts to eradicate it. Low vitamin D levels have been identified as a risk factor for tuberculosis infection and disease. The human cathelicidin LL-37 has both antimicrobial and immunomodulatory properties and is dependent on vitamin D status. This systematic review attempts to compare vitamin D andLL-37 levels among adult pulmonary tuberculosis patients to non-pulmonary TB individuals between 16-75 years globally and to determine the association between vitamin D and cathelicidin and any contributing factor among the two study groups. METHODS/DESIGN: We performed a search, through PubMed, HINARI, Google Scholar, EBSCOhost, and databases. A narrative synthesis through evaluation of vitamin D and LL-37 levels, the association of vitamin D and LL-37, and other variables in individual primary studies were performed. A random-effect model was performed and weighted means were pooled at a 95% confidence interval. This protocol is registered under the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42019127232. RESULTS: Of the 2507 articles selected12 studies were eligible for the systematic review and of these only nine were included in the meta-analysis for vitamin D levels and six for LL-37 levels. Eight studies were performed in Asia, three in Europe, and only one study in Africa. The mean age of the participants was 37.3±9.9 yrs. We found low vitamin D and high cathelicidin levels among the tuberculosis patients compared to non-tuberculosis individuals to non-tuberculosis. A significant difference was observed in both vitamin D and LL-37 levels among tuberculosis patients and non-tuberculosis individuals (p = < 0.001). CONCLUSION: This study demonstrated that active pulmonary tuberculosis disease is associated with hypovitaminosis D and elevated circulatory cathelicidin levels with low local LL-37 expression. This confirms that vitamin D status has a protective role against tuberculosis disease.
Subject(s)
Antimicrobial Cationic Peptides/blood , Tuberculosis, Pulmonary/blood , Vitamin D Deficiency/blood , Vitamin D/blood , Adolescent , Adult , Aged , Female , Global Health/statistics & numerical data , Humans , Male , Middle Aged , Tuberculosis, Pulmonary/epidemiology , Vitamin D Deficiency/epidemiology , CathelicidinsABSTRACT
BACKGROUND: Acute pancreatitis (AP), one of the most common clinical emergencies, is characterized by variable clinical features and inadequate diagnostic methods. At present, the commonly used indicators do not have high specificity and do not necessarily reflect disease severity. We therefore aimed to investigate diagnostic and prognostic value of plasma procalcitonin, heparin-binding protein, and interleukin-6 for acute pancreatitis by separate detection and joint detection. METHODS: The study involved 451 participants, including 343 AP patients and 108 healthy controls. We analyzed the association of the three biomarkers with the severity and prognosis of AP. RESULTS: A statistically significant increase in the mean plasma analyte levels was detected in the study group compared to the control group. Multivariate comparison showed that plasma levels of PCT, HBP, and IL-6 were all significantly different among the three groups at different sampling times (1st, 3rd, 7th, and 10th day of admission) (p < 0.01). The combination of the three indicators had significantly higher diagnostic value than either the individual markers or pairwise combinations (p < 0.001). The levels of the three were all significantly higher in severe acute pancreatitis (SAP) patients than in non-SAP patients (p < 0.001); meanwhile, patients with high levels had a worse prognosis than those with low levels (p < 0.05). In multivariate analysis adjusted for age and sex, high levels of PCT, HBP, and IL-6 were found to be independently associated with the development of AP. CONCLUSIONS: It dramatically improved the diagnostic power of AP when PCT, HBP, and IL-6 were combined; high PCT, HBP, and IL-6 levels within 3 days of admission may be the potentially useful indicators for predicting SAP.
Subject(s)
Antimicrobial Cationic Peptides/blood , Biomarkers/blood , Interleukin-6/blood , Pancreatitis/blood , Procalcitonin/blood , Adult , Blood Proteins , Case-Control Studies , Female , Humans , Male , Middle Aged , Multivariate Analysis , PrognosisABSTRACT
Chronic exposure to high circulating glucocorticoid or ghrelin concentrations increases food intake, weight gain and adiposity, suggesting that ghrelin could contribute to the metabolic effects of chronic glucocorticoids. In male mice, however, blocking ghrelin receptor (GHSR) signaling increased the weight gain and adiposity induced by chronic corticosterone (CORT), rather than attenuating them. In the current study, we investigated the role of GHSR signaling in the metabolic effects of chronic exposure to high circulating CORT in female mice. To do this, female WT and GHSR KO mice were treated with either CORT in a 1% ethanol (EtOH) solution or 1% EtOH alone in their drinking water for 32 days (n = 5-8/group). Body weight, food, and water intake as well as vaginal cyclicity were assessed daily. As expected, CORT treatment-induced significant increases in body weight, food intake, adiposity and also impaired glucose tolerance. In contrast to results observed in male mice, WT and GHSR KO female mice did not differ on any of these parameters. Neither plasma levels of ghrelin, LEAP-2, the endogenous GHSR antagonist produced by the liver, nor their ratio were altered by chronic glucocorticoid exposure. In addition, CORT treatment disrupted vaginal cyclicity, produced a reduction in sucrose consumption and increased locomotor activity regardless of genotype. Chronic CORT also decreased exploration in WT but not GHSR KO mice. Collectively, these data suggest that most metabolic, endocrine, reproductive and behavioral effects of chronic CORT exposure are independent of GHSR signaling in female mice.
Subject(s)
Corticosterone/administration & dosage , Obesity/etiology , Receptors, Ghrelin/physiology , Signal Transduction/physiology , Adiposity/drug effects , Animals , Antimicrobial Cationic Peptides/blood , Behavior, Animal/drug effects , Corticosterone/blood , Eating/drug effects , Female , Ghrelin/blood , Mice , Mice, Knockout , Receptors, Ghrelin/deficiency , Receptors, Ghrelin/genetics , Weight Gain/drug effectsABSTRACT
Ghrelin and its endogenous antagonist liver-expressed antimicrobial peptide-2 (LEAP-2) are involved in GH secretion and glucose/lipids metabolism. LEAP-2 expression in conditions of metabolic impairment may be upregulated, usually pairing with a concomitant reduction in ghrelin secretion. Adult growth hormone deficiency (aGHD) is characterized by insulin resistance, weight gain, and increased fat mass. Therefore, the primary endpoint of this cross-sectional observational pilot study was to compare circulating LEAP-2 and ghrelin levels in aGHD and healthy controls. Thirty patients were included in the study. Group A included adult GHD: 15 patients, 8 females, and 7 males. Median and interquartile range age of the group was 53 (41-57) years, while BMI was 27.1 (25-35) kg/m2 . Group B was formed by 15 healthy controls (10 females and 5 males). Median and interquartile range age was 47 (36-57) years, while BMI 22.9 (20.8-33.1) kg/m2 . They were evaluated for serum glucose and insulin, HOMA-index, QUICKI-index, total/LDL/HDL cholesterol, triglycerides, IGF-1, ghrelin, and LEAP-2. Ghrelin levels in the aGHD group were significantly lower than in healthy controls. In contrast, LEAP-2 showed a trend toward higher levels, although the differences were not significant. However, the LEAP-2/Ghrelin ratio was significantly higher in aGHD. No significant correlations between ghrelin and LEAP-2 with BMI and HOMA index were found in aGHD population. However, a significant inverse correlation (r2 = 0.15, p = .047) between BMI and ghrelin was evidenced when considering the whole population. Taken together, these results may suggest a body adaptation to a metabolic scenario typical of aGHD. The decrease in ghrelin production could prevent further weight gain and fat mass increase, although losing its secretagogue effect.
Subject(s)
Antimicrobial Cationic Peptides/blood , Ghrelin/blood , Human Growth Hormone/deficiency , Adult , Blood Proteins , Body Mass Index , Case-Control Studies , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Pilot ProjectsABSTRACT
Adult-onset Still's disease (AOSD) is a systemic, multifactorial, autoinflammatory disease for which the etiopathogenesis is not well understood. Given the similarities in clinical and laboratory features between this disease and sepsis, and the differences in treatment strategies for these two diseases, specific diagnostic markers are crucial for the correct diagnosis and management of AOSD. Previous studies have shown plasma heparin-binding protein (HBP) is a promising potential biomarker for AOSD; thus, this study aimed to detect serum HBP levels in patients with AOSD or sepsis to assess its potential as a biomarker for differential diagnosis. We found that serum HBP levels were significantly higher in patients with active AOSD than that in those with inactive AOSD. Patients with sepsis had higher serum HBP levels compared with those who had active or inactive AOSD. We calculated the area under the receiver operating characteristic (ROC) curve to assess whether HBP could be used to differentiate active from inactive AOSD; this was 0.811 with sensitivity 0.650, specificity 0.811, and cutoff HBP value of 35.59 ng/ml. The area under the ROC curve for HBP as a biomarker to differentiate AOSD from sepsis was 0.653, with sensitivity 0.759, and specificity 0.552, and cutoff HBP value of 65.1 ng/ml. Taken together, the results of our study suggest that serum HBP could be a useful diagnostic biomarker to evaluate disease activity in patients with AOSD, and to differentiate AOSD from sepsis.
Subject(s)
Antimicrobial Cationic Peptides/blood , Biomarkers/blood , Sepsis/blood , Sepsis/diagnosis , Still's Disease, Adult-Onset/blood , Still's Disease, Adult-Onset/diagnosis , Adult , Blood Proteins , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Prognosis , ROC Curve , Reference Values , Severity of Illness Index , Still's Disease, Adult-Onset/etiology , Young AdultABSTRACT
BACKGROUND AND AIMS: Neutrophil-derived heparin binding protein (HBP; also known as azurocidin or CAP-37) is a key player in bacterial sepsis and a promising biomarker in severe infections. The aims of this study were to assess whether HBP is involved in the pathophysiology of COVID-19 and, if so, whether it can be used to predict severe disease preferably using a point-of-care test. METHODS: This was a prospective convenience sample study of biomarkers in patients admitted to Skåne University hospital in Sweden with a confirmed COVID-19 diagnosis. Plasma samples and clinical data were collected within 72h after admission, during hospital stay and at discharge. Plasma HBP concentrations samples were measured both with enzyme-linked immunosorbent assay (ELISA) and with a novel dry immunofluorescence analyzer (Joinstar) point-of-care test. RESULTS: Thirty-five COVID-19 patients were enrolled in the study. Twenty-nine patients had blood samples taken within 72h after admission. We compared the highest HBP value taken within 72h after admission in patients who eventually developed organ dysfunction (n = 23) compared to those who did not (n = 6), and found that HBP was significantly elevated in those who developed organ dysfunction (25.0 ng/mL (interquartile range (IQR) 16.6-48.5) vs 10.6 ng/mL (IQR 4.8-21.7 ng/mL), p = 0.03). Point-of-care test measurements correlated well with ELISA measurements (R = 0.83). HBP measured by the POC device predicted development of COVID-induced organ dysfunction with an AUC of 0.88 (95% confidence interval (CI) 0.70-1.0). CONCLUSIONS: HBP is elevated prior to onset of organ dysfunction in patients with severe COVID-19 using a newly developed point-of-care test and hence HBP could be used in a clinical setting as a prognostic marker in COVID-19.
Subject(s)
Antimicrobial Cationic Peptides/blood , COVID-19 Testing , COVID-19 , Point-of-Care Testing , SARS-CoV-2/metabolism , Aged , Aged, 80 and over , Biomarkers/blood , Blood Proteins , COVID-19/blood , COVID-19/diagnosis , Female , Humans , Intensive Care Units , Male , Middle Aged , Prospective Studies , Severity of Illness IndexABSTRACT
Neutropenia as an isolated clinical finding may include aetiologies ranging from severe disease to a transient condition, and differential diagnosis may be challenging. Previous data and clinical experience suggest that low levels of the neutrophil-derived protein human 18 kDa cathelicidin antimicrobial protein (hCAP-18) in the blood are predictive of more severe forms of neutropenia. The objective of this study was to present the results from a newly developed ELISA method that has been used in clinical routine in Sweden since 2018 for quantification of hCAP-18 in blood plasma. Using this method, we report that patients with severe disease analysed during the study period presented with low or undetectable levels of blood plasma hCAP-18, validating its use as screening tool for severe neutropenia. Furthermore, neutropenic patients as a group displayed lower levels of hCAP-18 as compared to blood donors. Within the group of neutropenic patients, those with neutrophil antibodies displayed significantly higher hCAP-18 levels compared to patients with idiopathic neutropenia. By including an analysis of hCAP-18 in the primary investigation of neutropenia, an increased accuracy in differential diagnosis is achieved, thus contributing to reduced costs of neutropenia management.
Subject(s)
Antimicrobial Cationic Peptides/blood , Blood Proteins/metabolism , Neutropenia/blood , Aged , Aged, 80 and over , Antibodies/metabolism , Child , Child, Preschool , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Infant , Male , Middle Aged , Neutrophils/metabolism , Plasma/metabolism , CathelicidinsABSTRACT
Recent publications on the probable role of heparin-binding protein (HBP) as a biomarker in sepsis prompted us to investigate its diagnostic and prognostic performance in severe COVID-19. HBP and IL-6 were measured by immunoassays at admission and on day 7 in 178 patients with pneumonia by SARS-CoV-2. Patients were classified into non-sepsis and sepsis as per the Sepsis-3 definitions and were followed up for the development of severe respiratory failure (SRF) and for outcome. Results were confirmed by multivariate analyses. HBP was significantly higher in patients classified as having sepsis and was negatively associated with the oxygenation ratio and positively associated with creatinine and lactate. Logistic regression analysis evidenced admission HBP more than 18 ng/ml and IL-6 more than 30 pg/ml as independent risk factors for the development of SRP. Their integration prognosticated SRF with respective sensitivity, specificity, positive predictive value, and negative predictive 59.1%, 96.3%, 83.9%, and 87.8%. Cox regression analysis evidenced admission HBP more than 35 ng/ml and IL-6 more than 30 pg/ml as independent risk factors for 28-day mortality. Their integration prognosticated 28-day mortality with respective sensitivity, specificity, positive predictive value, and negative predictive value 69.2%, 92.7%, 42.9%, and 97.5%. HBP remained unchanged over-time course. A prediction score of the disposition of patients with COVID-19 is proposed taking into consideration admission levels of IL-6 and HBP. Using different cut-offs, the score may predict the likelihood for SRF and for 28-day outcome.
Subject(s)
Antimicrobial Cationic Peptides/blood , COVID-19/blood , Interleukin-6/blood , Respiratory Insufficiency/blood , Adult , Biomarkers/blood , Blood Proteins , COVID-19/diagnosis , COVID-19/mortality , COVID-19/physiopathology , Female , Humans , Male , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Predictive Value of Tests , Prognosis , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/mortality , Respiratory Insufficiency/physiopathology , SARS-CoV-2/isolation & purification , Sepsis/blood , Sepsis/diagnosis , Sepsis/mortality , Sepsis/physiopathologyABSTRACT
CAMP (Cathelicidin antimicrobial peptide) is synthesized and secreted by adipocytes and involved in adipose tissue (AT) innate immune response and host defense of subcutaneous AT against Gram positive bacteria. Data on the regulation of CAMP in obesity and during weight loss are scarce and reference values do not exist. Serum CAMP levels (ELISA) and AT gene expression levels (quantitative real time PCR) were investigated in two large and longitudinal (12 months) cohorts of severely obese patients undergoing either a low calorie diet (LCD; n=79) or bariatric surgery (BS; n=156). The impact of metabolic factors on CAMP expression in vitro was investigated in differentiated 3T3-L1 adipocytes. CAMP serum levels significantly increased after BS but not during LCD. Females had lower CAMP serum levels and lower gene expression levels in subcutaneous AT. CAMP was positively correlated to unfavorable metabolic factors/adipokines and negatively to favorable factors/adipokines. CAMP gene expression was higher in subcutaneous than in visceral AT but serum CAMP levels were not correlated to levels of AT gene expression. While certain bile acids upregulated CAMP expression in vitro, high glucose/insulin as well as GLP-1 had an inhibitory effect. There exist gender-specific and AT compartment-specific effects on the regulation of CAMP gene expression. Weight loss induced by BS (but not by LCD) upregulated CAMP serum levels suggesting the involvement of weight loss-independent mechanisms in CAMP regulation such as bile acids, incretins and metabolic factors. CAMP might represent an adipokine at the interface between metabolism and innate immune response.