adrenomedullin and Bacterial-Infections

Invasive bacterial infections (IBI) in children present a difficult clinical challenge. They are often life-threatening, however in the early stages they can be hard to differentiate from benign viral infections. This leaves clinicians with the risk of missing a serious IBI diagnosis or inappropriately using antimicrobials in a child with a viral infection- contributing to the ongoing development of increased antimicrobial resistance. Hence, biomarkers which could aid in early detection of IBI and differentiation from viral infections are desirable. Mid-Regional pro-Adrenomedullin (MR-proADM) is a biomarker which has been associated with IBI. The aim of this systematic review was to determine its diagnostic accuracy in identifying children with IBI.. A strategy was devised to search online databases MEDLINE, Embase, Web of Science and Scopus for human clinical trials reporting the accuracy of MR-proADM in children. Against predesigned inclusion and exclusion criteria full texts were selected for inclusion and data extraction. True positives, false positives, true negatives and false negatives were extracted from each included study to fill 2 × 2 tables. Using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool methodological quality of each study was assessed.. A total of 501 articles were initially identified. After the removal of duplicates and abstract screening 11 texts were fully reviewed and four texts (totaling 1404 patients) were included in the systematic analysis. Only one study was of a high quality and that study accounted for the vast majority of patients. A single study reported the diagnostic accuracy of MR-proADM for invasive bacterial infection reporting an Area under the Curve of 0.69. The paucity of available studies made meta-analysis and studies of heterogeneity impossible.. There is a paucity of research regarding the diagnostic accuracy of MR-proADM in the diagnosis of invasive bacterial infections in children. Initial results would suggest that MR-proADM testing alone is poor at identifying IBI in young children. It remains unclear if MR-proADM performs differently in older children or in children with signs and symptoms of IBI.. PROSPERO CRD42018096295 .

Topics: Adrenomedullin; Anti-Infective Agents; Bacterial Infections; Biomarkers; Child; Child, Preschool; Early Diagnosis; Humans

Sepsis is characterised by organ dysfunction resulting from infection, with no reliable single objective test and current diagnosis based on clinical features and results of investigations. In the ED, investigations may be conducted to diagnose infection as the cause of the presenting illness, identify the source, distinguish sepsis from uncomplicated infection (i.e. without organ dysfunction) and/ or risk stratification. Appropriate sample collection for microbiological testing remains key for subsequent confirmation of diagnosis and rationalisation of antimicrobials. Routine laboratory investigations such as creatinine, bilirubin, platelet count and lactate are now critical elements in the diagnosis of sepsis and septic shock. With no biomarker sufficiently validated to rule out bacterial infection in the ED, there remains substantial interest in biomarkers representing various pathogenic pathways. New technologies for screening multiple genes and proteins are identifying unique network 'signatures' of clinical interest. Other future directions include rapid detection of bacterial DNA in blood, genes for antibiotic resistance and EMR-based computational biomarkers that collate multiple information sources. Reliable, cost-effective tests, validated in the ED to promptly and accurately identify sepsis, and to guide initial antibiotic choices, are important goals of current research efforts.

Topics: Adrenomedullin; Anti-Bacterial Agents; Bacterial Infections; Biomarkers; C-Reactive Protein; Calcitonin; Emergency Service, Hospital; Humans; Lactic Acid; Microbial Sensitivity Tests; Protein Precursors; Sepsis

Used appropriately, biomarkers improve the assessment of respiratory tract infections and sepsis. Most prominently, circulating procalcitonin levels increase by a factor of several tens of thousands during sepsis. Using a sensitive assay, procalcitonin safely and markedly reduces antibiotic usage in respiratory tract infections and nonbacterial meningitis. Procalcitonin is the protopye of hormokine mediators. The term "hormokine" encompasses the cytokine-like behaviour of hormones during inflammation and infections. The concept is based on a ubiquitous expression of calcitonin peptides during sepsis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Other peptides share some features of hormokines, e.g. natriuretic peptide and copeptin. Hormokines are not only biomarkers of infection but are also pivotal inflammatory mediators. Like all mediators, their role during systemic infections is basically beneficial, possibly to combat invading microbes. However, at increased levels they can become harmful for their host. Multiple mechanisms of action were proposed. In several animal models the modulation and neutralisation of hormokines during infection was shown to improve survival, and thus might open new treatment options for severe infections, especially of the respiratory tract.

Topics: Adrenomedullin; Animals; Anti-Bacterial Agents; Bacterial Infections; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Community-Acquired Infections; Critical Pathways; Diagnosis, Differential; Glycopeptides; Humans; Natriuretic Peptides; Pneumonia, Bacterial; Predictive Value of Tests; Prognosis; Protein Precursors; Respiratory Tract Infections; Sepsis

The study was performed to assess the usefulness of two new biomarkers, midregional pro-adrenomedullin (MR-pro-ADM) and C-pro-endothelin-1 (CT-pro-ET-1), in predicting bacterial infection (BI) and especially invasive bacterial infection (IBI) in well-appearing infants with fever without source (FWS). For this purpose, a multicenter prospective study was conducted between February 2008 and March 2009 including well-appearing infants less than 36 months of age with FWS. MR-pro-ADM, CT-pro-ET-1, procalcitonin (PCT), CRP, and WBC were measured and compared. Among the 1,035 infants included, a bacterial infection was diagnosed in 75 patients (7.2 %), and 16 (1.54 %) had an invasive bacterial infection (bacterial meningitis, 8; occult bacteremia, 6; and sepsis, 1). MR-pro-ADM and CT-pro-ET-1 levels were less reliable for diagnosis than the other biomarkers. The area under receiver operating characteristic curve for infants with BI and IBI was 0.59 (95 % confidence interval (CI) 0.52-0.67) and 0.63 (95 % CI 0.46-0.80) for MR-pro-ADM and 0.58 (95 % CI 0.51-0.66) and 0.62 (95 % CI 0.47-0.67) for CT-pro-ET-1, respectively. Multivariate analysis showed that PCT ≥ 0.5 ng/mL, CRP ≥ 40 mg/L, and CT-pro-ET-1 ≥ 105 pmol/mL were independent risk factors for having a BI (odds ratio (OR) 6.12, 3.61, and 2.84, respectively). PCT was the only independent risk factor for having an IBI (OR 17.53 if PCT ≥ 0.5 ng/mL).. Although baseline MR-pro-ADM and CT-pro-ET-1 levels are significantly elevated in well-appearing febrile infants with a bacterial infection, their overall performance as diagnostic markers is very poor.

Topics: Adrenomedullin; Bacterial Infections; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Endothelin-1; Female; Fever of Unknown Origin; Follow-Up Studies; Humans; Infant; Leukocyte Count; Logistic Models; Male; Multivariate Analysis; Odds Ratio; Peptide Fragments; Prospective Studies; Protein Precursors; ROC Curve; Severity of Illness Index

Current sepsis guidelines do not provide good risk stratification of subgroups in whom prompt IV antibiotics and fluid resuscitation might of benefit. We evaluated the utility of mid-regional pro-adrenomedullin (MR-proADM) in identification of patient subgroups at risk of requiring PICU or high-dependency unit (HDU) admission or fluid resuscitation.. Secondary, nonprespecified analysis of prospectively collected dataset.. Pediatric Emergency Department in a United Kingdom tertiary center.. Children less than 16 years old presenting with fever and clinical indication for venous blood sampling ( n = 1,183).. None.. Primary outcome measures were PICU/HDU admission or administration of fluid resuscitation, with a secondary outcome of definite or probable bacterial infection. Biomarkers were measured on stored plasma samples and children phenotyped into bacterial and viral groups using a previously published algorithm. Of the 1,183 cases, 146 children (12.3%) required fluids, 48 (4.1%) were admitted to the PICU/HDU, and 244 (20.6%) had definite or probable bacterial infection. Area under the receiver operating characteristic (AUC) was used to assess performance. MR-proADM better predicted fluid resuscitation (AUC, 0.73; 95% CI, 0.67-0.78), than both procalcitonin (AUC, 0.65; 95% CI, 0.59-0.71) and Pediatric Early Warning Score (PEWS: AUC, 0.62; 95% CI, 0.56-0.67). PEWS alone showed good accuracy for PICU/HDU admission 0.83 (0.78-0.89). Patient subgroups with high MR-proADM (≥ 0.7 nmol/L) and high procalcitonin (≥ 0.5 ng/mL) had increased association with PICU/HDU admission, fluid resuscitation, and bacterial infection compared with subgroups with low MR-proADM (< 0.7 nmol/L). For children with procalcitonin less than 0.5 ng/mL, high MR-proADM improved stratification for fluid resuscitation only.. High MR-proADM and high procalcitonin were associated with increased likelihood of subsequent disease progression. Incorporating MR-proADM into clinical risk stratification may be useful in clinician decision-making regarding initiation of IV antibiotics, fluid resuscitation, and escalation to PICU/HDU admission.

Topics: Adolescent; Adrenomedullin; Anti-Bacterial Agents; Bacterial Infections; Biomarkers; Child; Cohort Studies; Early Warning Score; Emergency Service, Hospital; Fever; Humans; Procalcitonin; Prognosis; Protein Precursors; Risk Assessment; United Kingdom

The early recognition of invasive bacterial infections (IBI) in children can be difficult. Clinically it is often challenging to differentiate between the early stages of an IBI and a benign self-limiting viral infection. These challenges mandate a cautious approach resulting in the overuse of antimicrobial drugs with resultant antimicrobial resistance. Due to these challenges, there is growing research into the role of biomarkers for the early identification of children with IBI. Earlier and more accurate diagnoses may lead to improved clinical outcomes for children and reduced antimicrobial resistance. Mid-regional pro-adrenomedullin (MR-proADM) is a biomarker that has been shown to be elevated in patients with IBI. The aim of this systematic review is to determine the diagnostic accuracy of MR-proADM at identifying children with IBI.. To identify relevant studies we will search MEDLINE, Embase, Web of Science and Scopus from 1980 to the present day for all human clinical trials involving children that report the test accuracy of MR-proADM. We will include case-control studies, cohort studies and randomised control trials reported in any language. In addition, we will hand-search reference lists and grey literature including conference abstracts and web searches. Two reviewers will independently screen study titles and abstracts for eligibility followed by full-text assessment and data extraction including population, setting, timing and use of index test and reference standard used. Methodological quality will be assessed, by two authors, according to the revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2), any discrepancies will be resolved by a third author. The following test characteristics will be extracted into 2 × 2 tables for all included studies: true positives, false positives, true negatives and false negatives. Study-specific estimates of sensitivity and specificity with 95% confidence intervals will be displayed in forest plots.. This review will report the normal ranges for MR-proADM in health and the diagnostic accuracy of MR-proADM at identifying children with IBI. The review will help to define where in the diagnostic pathway MR-proADM could be useful including potential as a point-of-care test for children at first presentation with IBI.. PROSPERO CRD42018096295.

Topics: Adrenomedullin; Bacterial Infections; Child; Cohort Studies; Diagnostic Tests, Routine; Humans; Meta-Analysis as Topic; Sensitivity and Specificity; Systematic Reviews as Topic

Proadrenomedullin N-terminal 20 peptide (PAMP) is a regulatory peptide that is found in various cell types. It is involved in many biological activities and is rich in basic and hydrophobic amino acids, a common feature of antimicrobial peptides (AMPs). In this study, the cell selectivity and antimicrobial mechanism of PAMP and its C-terminal peptide, PAMP(9-20), were investigated. PAMP and PAMP(9-20) displayed potent antimicrobial activity (minimum inhibitory concentration: 4-32 μM) against standard bacterial strains, but showed no hemolytic activity even at the highest tested concentration of 256 μM. PAMP(9-20) showed 2- to 4-fold increase in antimicrobial activity against gram-negative bacteria compared to PAMP. Cytoplasmic membrane depolarization, leakage of calcein dye from membrane mimic liposomes, SYTOX Green uptake, membrane permeabilization, and flow cytometry studies indicated that the major target of PAMP and PAMP(9-20) is not the microbial cell membrane. Interestingly, laser-scanning confocal microscopy demonstrated that FITC-labeled PAMP and PAMP(9-20) enter the cytoplasm of Escherichia coli similar to buforin-2, and gel retardation assay indicated that PAMP and PAMP(9-20) effectively bind to bacterial DNA. These results suggest that the intracellular target mechanism is responsible for the antimicrobial action of PAMP and PAMP(9-20). Collectively, PAMP and PAMP(9-20) could be considered promising candidates for the development of new antimicrobial agents.

Topics: Adrenomedullin; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Outer Membrane; DNA, Bacterial; Hemolysis; Microbial Sensitivity Tests; Peptide Fragments; Protein Precursors; Sheep

To assess the usefulness of procalcitonin, pro-adrenomedullin and pro-atrial natriuretic peptide as predictors of need for mechanical ventilation and postoperative complications (need for inotropic support and bacterial infection) in critically ill pediatric patients after cardiopulmonary bypass.. A prospective, observational study.. Pediatric intensive care unit.. Patients under 18 years old admitted after cardiopulmonary bypass.. Serum levels of procalcitonin, pro-adrenomedullin and pro-atrial natriuretic peptide were determined immediately after bypass and at 24-36 hours. Their values were correlated with the need for mechanical ventilation, inotropic support and bacterial infection. One hundred eleven patients were recruited. Septal defects (30.6%) and cardiac valve disease (17.1%) were the most frequent pathologies. 40.7% required mechanical ventilation, 94.6% inotropic support and 15.3% presented invasive bacterial infections. Pro-adrenomedullin and pro-atrial natriuretic peptide showed significant high values in patients needing mechanical ventilation. Cut-off values higher than 1.22 nmol/L and 215.3 pmol/L, respectively for each biomarker, may indicate need for mechanical ventilation with an AUC of 0.721 and 0.746 at admission and 0.738 and 0.753 at 24-36 hours, respectively but without statistical differences. Pro-adrenomedullin and procalcitonin showed statistically significant high values in patients with bacterial infections.. After bypass, pro-adrenomedullin and pro-atrial natriuretic peptide are suitable biomarkers to predict the need for mechanical ventilation. Physicians should be alert if the values of these markers are high so as not to progress to early extubation. Procalcitonin is useful for predicting bacterial infection. This is a preliminary study and more clinical studies should be done to confirm the value of pro-adrenomedullin and pro-atrial natriuretic peptide as biomarkers after cardiopulmonary bypass.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Bacterial Infections; Biomarkers; Cardiopulmonary Bypass; Child; Child, Preschool; Humans; Infant; Myocardial Contraction; Pediatrics; Postoperative Care; Postoperative Complications; Procalcitonin; Prognosis; Prospective Studies; Protein Precursors

Rapid diagnosis of bacterial infections is crucial for adequate antibiotic treatment. Serum molecules such as Procalcitonin (PCT) have been used as biomarkers of infection. Recently, the mid-regional pro-Adrenomedullin (MR-proADM) has been evaluated in combination with PCT for sepsis diagnosis. The diagnostic role of PCT and MR-proADM both in sepsis and in localized infections together with their contribution to effective antibiotic therapy has been evaluated. One hundred and eighty-two patients with bacterial infection has been enrolled: PCT and MR-proADM were measured at admission (T = 0), at 12-24 h (T = 1) and in the third or fifth day of antibiotic therapy (T = 3-5). ROC curve (receiver operating characteristic) and post-test probability were calculated. MR-proADM increased with the severity of the infection. PCT resulted significantly higher in sepsis than localized infection. After antibiotic therapy, PCT significantly decreased in localized respiratory infections and in sepsis, while MR-proADM decreased significantly after antibiotic therapy only in patients with severe sepsis/septic shock. The threshold values of PCT and MR-proADM were >0.1 ng/mL and >0.8 nmol/L, respectively. The combined use of PCT and MR-proADM increased the post-test probability of the diagnosis of bacterial infections compared to PCT alone. In conclusion, PCT and MR-proADM combination improves the diagnosis of bacterial infection and contribute to prognosis and antibiotic therapy effectiveness.

Topics: Adolescent; Adrenomedullin; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Female; Humans; Male; Middle Aged; Prognosis; Protein Precursors; Sepsis; Young Adult

Topics: Adrenomedullin; Bacterial Infections; Endothelin-1; Female; Fever of Unknown Origin; Humans; Male; Peptide Fragments; Protein Precursors

Topics: Adrenomedullin; Bacterial Infections; Endothelin-1; Female; Fever of Unknown Origin; Humans; Male; Peptide Fragments; Protein Precursors

To evaluate the serum levels of three precursors of vasoactive peptide as diagnostic markers for neonatal infections.. Overall, 356 neonates (160 without infection, 114 with mild infections and 82 with severe infections) were enrolled in this study. Their serum levels of mid-regional pro-adrenomedullin (MR-pro-ADM), C-terminal pro-endothelin-1 (CT-pro-ET-1) and mid-regional pro-atrial natriuretic peptide (MR-pro-ANP) were measured by immunoassay, and receiver operating curve analysis was performed for each biomarker to evaluate their diagnostic values for neonatal infection.. The serum levels of MR-pro-ADM (2.079 ± 1.195 nM), CT-pro-ET-1 (109.4 ± 62.9 pM) and MR-pro-ANP (1221.4 ± 725.0 pM) in the severe infection group were significantly higher than those in the mild infection group (1.025 ± 0.421 nM, 86.7 ± 51.8 pM, and 687.6 ± 575.7 pM, respectively) and in the non-infection group (0.853 ± 0.488 nM, 51.3 ± 40.6 pM, and 943.3 ± 847.3 pM, respectively) (p < 0.01-0.001). Their areas under the curve were 0.72, 0.76 and 0.61, respectively. Among them, CT-pro-ET-1 had the highest sensitivity (82.65%), whereas MR-pro-ADM had the highest specificity (86.25%).. MR-pro-ADM, CT-pro-ET-1 and MR-pro-ANP may serve as useful laboratory markers to indicate bacterial infection in neonates.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Bacterial Infections; Biomarkers; C-Reactive Protein; Endothelin-1; Female; Humans; Infant, Newborn; Male; Peptide Fragments; Protein Precursors; ROC Curve; Sensitivity and Specificity; Severity of Illness Index

Many surface epithelial cells express adrenomedullin (AM) and it is postulated that it may have an important protective role. This peptide has many properties in common with other cationic antimicrobial peptides including the human beta-defensins. Antimicrobial activity against members of the human skin, oral, respiratory tract and gastric microflora has been demonstrated. Both pathogenic and commensal strains of bacteria are sensitive; Gram-positive and Gram-negative bacteria being equally susceptible. No activity against the yeast Candida albicans was observed. Minimum inhibitory and minimum bacteriocidal concentrations range from 7.75 x 10(-4) to 12.5 and 0.003 to >25.0 microg ml(-1), respectively. On exposure of oral, skin and gastric epithelial cells to whole cells and culture supernatants from bacteria isolated from these sites an increase in AM peptide and gene expression has been observed. No upregulation was detected with C. albicans. In cultured cells and an animal infection model increased AM peptide and gene expression has been demonstrated using immunohistochemical and in situ hybridization techniques. These collective findings suggest that AM represents a new category of antimicrobial peptide, which contributes to the mucosal host defence system.

Topics: Adrenomedullin; Animals; Anti-Bacterial Agents; Bacterial Infections; beta-Defensins; Cattle; Host-Parasite Interactions; Humans; Ileum; Immunity, Mucosal; Peptides

Although sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase, the mechanism responsible for the transition from the hyperdynamic to the hypodynamic state remains unknown. Since recent studies have shown that adrenomedullin (ADM), a novel potent vasodilatory peptide, is upregulated during sepsis, the aim of this study was to determine whether the reduced vascular responsiveness to ADM is associated with the transition from the hyperdynamic phase to the hypodynamic phase of sepsis.. Adult male Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 and 10 h (i.e., the hyperdynamic phase of sepsis) or 20 h (the hypodynamic phase) after CLP, the thoracic aorta or small intestine was harvested and preconstricted with norepinephrine. Adrenomedullin (10(-7) M) was applied and the percentage of ADM-induced vascular relaxation in the aortic ring and isolated small intestine was determined.. The responsiveness to ADM in the thoracic aorta was not altered at 5-10 h, but decreased significantly at 20 h after CLP. Although ADM-induced relaxation in resistance blood vessels of the small intestine did not change at 5 h, it decreased markedly at 10 and 20 h after the onset of sepsis.. Since the transition from hyperdynamic to hypodynamic sepsis takes place between 10 and 20 h after CLP, it is likely that reduced vascular responsiveness to ADM may be responsible for such an event during the course of polymicrobial sepsis. In view of this, maintenance of vascular ADM responsiveness by pharmacologic agents appears to be a novel approach for preventing or delaying the occurrence of hypodynamic sepsis and septic shock.

Topics: Adrenomedullin; Animals; Aorta, Thoracic; Bacterial Infections; Blood Vessels; In Vitro Techniques; Intestines; Male; Peptides; Rats; Rats, Sprague-Dawley; Vasodilation; Vasodilator Agents