Procalcitonin, mid-regional proadrenomedullin and C-reactive protein in predicting treatment outcome in community-acquired febrile urinary tract infection.

BACKGROUND: A reduction in duration of antibiotic therapy is crucial in minimizing the development of antimicrobial resistance, drug-related side effects and health care costs. The minimal effective duration of antimicrobial therapy for febrile urinary tract infections (fUTI) remains a topic of uncertainty, especially in male patients, those of older age or with comorbidities. Biomarkers have the potential to objectively identify the optimal moment for cessation of therapy. METHODS: A secondary analysis of a randomized placebo-controlled trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days. Patients indicated to receive antimicrobial treatment for more than 14 days were excluded from randomization. The biomarkers procalcitonin (PCT), mid-regional proadrenomedullin (MR-proADM), and C-reactive protein (CRP) were compared in their ability to predict clinical cure or failure through the 10-18 day post-treatment visit. RESULTS: Biomarker concentrations were measured in 249 patients, with a clinical cure rate of 94% in the 165 randomized and 88% in the 84 non-randomized patients. PCT, MR-proADM and CRP concentrations did not differ between patients with clinical cure and treatment failure, and did not predict treatment outcome, irrespective of 7 or 14 day treatment duration (ROCAUC 0.521; 0.515; 0.512, respectively). PCT concentrations at presentation were positively correlated with bacteraemia (τ = 0.33, p < 0.001) and presence of shaking chills (τ = 0.25, p < 0.001), and MR-proADM levels with length of hospital stay (τ = 0.40, p < 0.001), bacteraemia (τ = 0.33, p < 0.001), initial intravenous treatment (τ = 0.22, p < 0.001) and time to defervescence (τ = 0.21, p < 0.001). CRP did not display any correlation to relevant clinical parameters. CONCLUSIONS: Although the biomarkers PCT and MR-proADM were correlated to clinical parameters indicating disease severity, they did not predict treatment outcome in patients with community acquired febrile urinary tract infection who were treated for either 7 or 14 days. CRP had no added value in the management of patients with fUTI. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

Biomarkers and clinical scores to identify patient populations at risk of delayed antibiotic administration or intensive care admission.

BACKGROUND: The performance of blood biomarkers (mid-regional proadrenomedullin (MR-proADM), procalcitonin (PCT), C-reactive protein (CRP), and lactate) and clinical scores (Sequential Organ Failure Assessment (SOFA), National Early Warning Score (NEWS), and quick SOFA) was compared to identify patient populations at risk of delayed treatment initiation and disease progression after presenting to the emergency department (ED) with a suspected infection. METHODS: A prospective observational study across three EDs. Biomarker and clinical score values were calculated upon presentation and 72 h, and logistic and Cox regression used to assess the strength of association. Primary outcomes comprised of 28-day mortality prediction and delayed antibiotic administration or intensive care (ICU) admission, whilst secondary outcomes identified subsequent disease progression. RESULTS: Six hundred eighty-four patients were enrolled with hospitalisation, ICU admission, and infection-related 28-day mortality rates of 72.8%, 3.4%, and 4.4%, respectively. MR-proADM and NEWS had the strongest association with hospitalisation and the requirement for antibiotic administration, whereas MR-proADM alone had the strongest association with ICU admission (OR [95% CI]: 5.8 [3.1 - 10.8]) and mortality (HR [95% CI]: 3.8 [2.2 - 6.5]). Patient subgroups with high MR-proADM concentrations (≥ 1.77 nmol/L) and low NEWS (< 5 points) values had significantly higher rates of ICU admission (8.1% vs 1.6%; p < 0.001), hospital readmission (18.9% vs. 5.9%; p < 0.001), infection-related mortality (13.5% vs. 0.2%; p < 0.001), and disease progression (29.7% vs. 4.9%; p < 0.001) than corresponding patients with low MR-proADM concentrations. ICU admission was delayed by 1.5 [0.25 - 5.0] days in patients with high MR-proADM and low NEWS values compared to corresponding patients with high NEWS values, despite similar 28-day mortality rates (13.5% vs. 16.5%). Antibiotics were withheld in 17.4% of patients with high MR-proADM and low NEWS values, with higher subsequent rates of ICU admission (27.3% vs. 4.8%) and infection-related hospital readmission (54.5% vs. 14.3%) compared to those administered antibiotics during ED treatment. CONCLUSIONS: Patients with low severity signs of infection but high MR-proADM concentrations had an increased likelihood of subsequent disease progression, delayed antibiotic administration or ICU admission. Appropriate triage decisions and the rapid use of antibiotics in patients with high MR-proADM concentrations may constitute initial steps in escalating or intensifying early treatment strategies.

The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study.

BACKGROUND: There is a lack of validated tools to assess potential disease progression and hospitalisation decisions in patients presenting to the emergency department (ED) with a suspected infection. This study aimed to identify suitable blood biomarkers (MR-proADM, PCT, lactate and CRP) or clinical scores (SIRS, SOFA, qSOFA, NEWS and CRB-65) to fulfil this unmet clinical need. METHODS: An observational derivation patient cohort validated by an independent secondary analysis across nine EDs. Logistic and Cox regression, area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves were used to assess performance. Disease progression was identified using a composite endpoint of 28-day mortality, ICU admission and hospitalisation > 10 days. RESULTS: One thousand one hundred seventy-five derivation and 896 validation patients were analysed with respective 28-day mortality rates of 7.1% and 5.0%, and hospitalisation rates of 77.9% and 76.2%. MR-proADM showed greatest accuracy in predicting 28-day mortality and hospitalisation requirement across both cohorts. Patient subgroups with high MR-proADM concentrations (≥ 1.54 nmol/L) and low biomarker (PCT < 0.25 ng/mL, lactate < 2.0 mmol/L or CRP < 67 mg/L) or clinical score (SOFA < 2 points, qSOFA < 2 points, NEWS < 4 points or CRB-65 < 2 points) values were characterised by a significantly longer length of hospitalisation (p < 0.001), rate of ICU admission (p < 0.001), elevated mortality risk (e.g. SOFA, qSOFA and NEWS HR [95%CI], 45.5 [10.0-207.6], 23.4 [11.1-49.3] and 32.6 [9.4-113.6], respectively) and a greater number of disease progression events (p < 0.001), compared to similar subgroups with low MR-proADM concentrations (< 1.54 nmol/L). Increased out-patient treatment across both cohorts could be facilitated using a derivation-derived MR-proADM cut-off of < 0.87 nmol/L (15.0% and 16.6%), with decreased readmission rates and no mortalities. CONCLUSIONS: In patients presenting to the ED with a suspected infection, the blood biomarker MR-proADM could most accurately identify the likelihood of further disease progression. Incorporation into an early sepsis management protocol may therefore aid rapid decision-making in order to either initiate, escalate or intensify early treatment strategies, or identify patients suitable for safe out-patient treatment.

Correction to: The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study.

In the publication of this article [1], there are two errors in contributing author affiliations. This has now been included in this correction article.

The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis - a secondary analysis of a large randomised controlled trial.

BACKGROUND: This study assessed the ability of mid-regional proadrenomedullin (MR-proADM) in comparison to conventional biomarkers (procalcitonin (PCT), lactate, C-reactive protein) and clinical scores to identify disease severity in patients with sepsis. METHODS: This is a secondary analysis of a randomised controlled trial in patients with severe sepsis or septic shock across 33 German intensive care units. The association between biomarkers and clinical scores with mortality was assessed by Cox regression analysis, area under the receiver operating characteristic and Kaplan-Meier curves. Patients were stratified into three severity groups (low, intermediate, high) for all biomarkers and scores based on cutoffs with either a 90% sensitivity or specificity. RESULTS: 1089 patients with a 28-day mortality rate of 26.9% were analysed. According to the Sepsis-3 definition, 41.2% and 58.8% fulfilled the criteria for sepsis and septic shock, with respective mortality rates of 20.0% and 32.1%. MR-proADM had the strongest association with mortality across all Sepsis-1 and Sepsis-3 subgroups and could facilitate a more accurate classification of low (e.g. MR-proADM vs. SOFA: N = 265 vs. 232; 9.8% vs. 13.8% mortality) and high (e.g. MR-proADM vs. SOFA: N = 161 vs. 155; 55.9% vs. 41.3% mortality) disease severity. Patients with decreasing PCT concentrations of either ≥ 20% (baseline to day 1) or ≥ 50% (baseline to day 4) but continuously high MR-proADM concentrations had a significantly increased mortality risk (HR (95% CI): 19.1 (8.0-45.9) and 43.1 (10.1-184.0)). CONCLUSIONS: MR-proADM identifies disease severity and treatment response more accurately than established biomarkers and scores, adding additional information to facilitate rapid clinical decision-making and improve personalised sepsis treatment.

The association of midregional pro-adrenomedullin (MR-proADM) at ICU admission and fluid overload in patients post elective cardiac surgery.

Postoperative fluid overload (FO) after cardiac surgery is common and affects recovery. Predicting FO could help optimize fluid management. This post-hoc analysis of the HERACLES randomized controlled trial evaluated the predictive value of MR-proADM for FO post-cardiac surgery. MR-proADM levels were measured at four different timepoints in 33 patients undergoing elective cardiac surgery. Patients were divided into FO (> 5% weight gain) and no-FO at ICU discharge. The primary outcome was the predictive power of MR-proADM at ICU admission for FO at discharge. Secondary outcomes included the predictive value of MR-proADM for FO on day 6 post-surgery and changes over time. The association between MR-proADM and FO at ICU discharge or day 6 post-surgery was not significant (crude odds ratio (cOR): 4.3 (95% CI 0.5-40.9, p = 0.201) and cOR 1.1 (95% CI 0.04-28.3, p = 0.954)). MR-proADM levels over time did not differ significantly between patients with and without FO at ICU discharge (p = 0.803). MR-proADM at ICU admission was not associated with fluid overload at ICU discharge in patients undergoing elective cardiac surgery. MR-proADM levels over time were not significantly different between groups, although elevated levels were observed in patients with FO.

Biomarkers and clinical scores to aid the identification of disease severity and intensive care requirement following activation of an in-hospital sepsis code.

BACKGROUND: Few validated biomarker or clinical score combinations exist which can discriminate between cases of infection and other non-infectious conditions following activation of an in-hospital sepsis code, as well as provide an accurate severity assessment of the corresponding host response. This study aimed to identify suitable blood biomarker (MR-proADM, PCT, CRP and lactate) or clinical score (SOFA and APACHE II) combinations to address this unmet clinical need. METHODS: A prospective, observational study of patients activating the Vall d'Hebron University Hospital sepsis code (ISC) within the emergency department (ED), hospital wards and intensive care unit (ICU). Area under the receiver operating characteristic (AUROC) curves, logistic and Cox regression analysis were used to assess performance. RESULTS: 148 patients fulfilled the Vall d'Hebron ISC criteria, of which 130 (87.8%) were retrospectively found to have a confirmed diagnosis of infection. Both PCT and MR-proADM had a moderate-to-high performance in discriminating between infected and non-infected patients following ISC activation, although the optimal PCT cut-off varied significantly across departments. Similarly, MR-proADM and SOFA performed well in predicting 28- and 90-day mortality within the total infected patient population, as well as within patients presenting with a community-acquired infection or following a medical emergency or prior surgical procedure. Importantly, MR-proADM also showed a high association with the requirement for ICU admission after ED presentation [OR (95% CI) 8.18 (1.75-28.33)] or during treatment on the ward [OR (95% CI) 3.64 (1.43-9.29)], although the predictive performance of all biomarkers and clinical scores diminished between both settings. CONCLUSIONS: Results suggest that the individual use of PCT and MR-proADM might help to accurately identify patients with infection and assess the overall severity of the host response, respectively. In addition, the use of MR-proADM could accurately identify patients requiring admission onto the ICU, irrespective of whether patients presented to the ED or were undergoing treatment on the ward. Initial measurement of both biomarkers might therefore facilitate early treatment strategies following activation of an in-hospital sepsis code.

Activation of chloride secretion via proteinase-activated receptor 2 in a human eccrine sweat gland cell line--NCL-SG3.

Proteinase-activated receptor 2 (PAR-2) has been shown to elicit secretion in a variety of secretory epithelial cells by the transepithelial movement of chloride ions across the apical membrane. However, it is not known whether these receptors are present and/or functional in the secretory epithelial cells of the human eccrine sweat gland. To investigate this possibility mRNA analysis, Ca2+ microspectrofluorimetry and the short circuit current (Isc) technique were used to quantify electrolyte transport in a cell line (NCL-SG3) derived from human eccrine sweat gland secretory epithelia. The results provided molecular and functional evidence of the presence of PAR-2 receptors in the NCL-SG3 cells and show that these receptors can activate transepithelial Cl- secretion possibly via Ca2+-activated Cl- channels.

Biomarker guided triage can reduce hospitalization rate in community acquired febrile urinary tract infection.

OBJECTIVES: Febrile urinary tract infections (fUTI) can often be treated safely with oral antimicrobials in an outpatient setting. However, a minority of patients develop complications that may progress into septic shock. An accurate assessment of disease severity upon emergency department (ED) presentation is therefore crucial in order to guide the most appropriate triage and treatment decisions. METHODS: Consecutive patients were enrolled with presumptive fUTI across 7 EDs in the Netherlands. The biomarkers mid-regional proadrenomedullin (MR-proADM), procalcitonin (PCT), C-reactive protein (CRP), and a clinical score (PRACTICE), were compared in their ability to predict a clinically severe course of fUTI, initial hospital admission and subsequent readmission using area under the receiver operating characteristic (AUROC) curves. RESULTS: Biomarker concentrations were measured in 313 patients, with 259 (83%) hospitalized upon ED presentation, and 54 (17%) treated as outpatients. Of these outpatients, 12 (22%) were later hospitalized. MR-proADM had the highest diagnostic accuracy for predicting a complicated fUTI (AUROC [95% CI]: 0.86 [0.79-0.92]), followed by PCT (AUROC [95% CI]: 0.69 [0.58-0.80]). MR-proADM concentrations were unique in being significantly elevated in patients directly admitted and in outpatients requiring subsequent hospitalization, compared to those completing treatment at home. A virtual triage algorithm with an MR-proADM cut-off of 0.80  nmol/L resulted in a hospitalization rate of 66%, with only 2% secondary admissions. CONCLUSION: MR-proADM could accurately predict a severe course in patients with fUTI, and identify greater patient numbers who could be safely managed as outpatients. An initial assessment on ED presentation may focus resources to patients with highest disease severities.

Mr-Proadm Elevation Upon Icu Admission Predicts the Outcome of Septic Patients and is Correlated with Upcoming Fluid Overload.

BACKGROUND: Among septic patients admitted to the intensive care unit (ICU), early recognition of those with the highest risk of death is of paramount importance. We evaluated the prognostic value of Procalcitonin (PCT), mid regional-proadrenomedullin (MR-proADM), copeptine and CT-proendothelin 1 (CT-ProET 1) concentrations. METHODS: This was a prospective cohort study, which included 173 septic patient admitted to one ICU. Blood samples for biomarker measurements were obtained upon admission and on day 5. The predictive value of each biomarker regarding the risk of death at day 28 was assessed. The fluid balance was evaluated from admission to day 5. RESULTS: All cause ICU mortality was 36.4%. All the biomarkers except CT-ProET-1 were significantly more elevated in the non-survivors than in the survivors upon day 1. This was especially true for MR-proADM (8.6 [5.9] vs. 4.4 [3.9] nmol/L; P < 0.0001) and for the CT-proET-1/MR-proADM ratio (52.9 [22.4] vs. 31.3 [26.6] arbitrary units; P < 0.0001). The best AUROCC values on day 1 were obtained with MR-ProADM and the CT-proET-1/MR-proADM ratio as well (0.75 [0.67-0.85] and 0.82 [0.75-0.89]; 95% CI, respectively). An improved accuracy was achieved on day 5. Moreover, MR-ProADM baseline levels and fluid balance over the 5-day period following ICU admission were strongly correlated (Rho = 0.41; P < 0.001). CONCLUSIONS: In patients admitted to the ICU with sepsis, MR-ProADM on admission was the best predictor of short-term clinical outcome if compared with others. This could be related to its ability to predict fluid sequestration.

A preliminary study of the short circuit current (Isc) responses of sweat gland cells from normal and anhidrotic horses to purinergic and adrenergic agonists.

The causal factors of equine anhidrosis have not yet been elucidated but defective electrolyte transport mechanisms in the gland are likely to be involved. To investigate this possibility, experiments were performed on cultured equine sweat gland epithelia from five free-sweating UK horses (3 intact males, 2 mares, aged 2-4 years) and from three free-sweating Singapore horses (1 intact male, 2 mares, aged 3-5 years) and three anhidrotic (Singapore) horses (1 intact male, 1 gelding, 1 mare, aged 3-6 years). Cultured cells from each animal were grown on permeable supports and loaded into Ussing chambers to quantify transepithelial resistance and agonist-induced electrolyte transport by the short circuit current (Isc) technique. Transepithelial resistances across the layers of cultured cells were not significantly different between cells from UK and Singapore free-sweating horses, but were significantly reduced in anhidrotic animals. Purinergic agonists added to the apical and basolateral aspects of the cultured cells caused similar increases in Isc between the two populations of unaffected cells, but Isc increases were significantly reduced in anhidrotic animals. Beta-adrenergic agonist stimulation of the anhidrotic cell layers failed to elicit any change in Isc. These pilot results not only confirm earlier conclusions from anatomical findings that failure in the secretory process occurs in anhidrosis but also indicate that both of the known ion transport mechanisms are involved. The trigger for these failures warrants further investigation.