Biomarker kinetics in the prediction of VAP diagnosis: results from the BioVAP study.
ABSTRACT: BACKGROUND:Prediction of diagnosis of ventilator-associated pneumonia (VAP) remains difficult. Our aim was to assess the value of biomarker kinetics in VAP prediction. METHODS:We performed a prospective, multicenter, observational study to evaluate predictive accuracy of biomarker kinetics, namely C-reactive protein (CRP), procalcitonin (PCT), mid-region fragment of pro-adrenomedullin (MR-proADM), for VAP management in 211 patients receiving mechanical ventilation for >72 h. For the present analysis, we assessed all (N = 138) mechanically ventilated patients without an infection at admission. The kinetics of each variable, from day 1 to day 6 of mechanical ventilation, was assessed with each variable's slopes (rate of biomarker change per day), highest level and maximum amplitude of variation (? (max)). RESULTS:A total of 35 patients (25.4 %) developed a VAP and were compared with 70 non-infected controls (50.7 %). We excluded 33 patients (23.9 %) who developed a non-VAP nosocomial infection. Among the studied biomarkers, CRP and CRP ratio showed the best performance in VAP prediction. The slope of CRP change over time (adjusted odds ratio [aOR] 1.624, confidence interval [CI]95% [1.206, 2.189], p = 0.001), the highest CRP ratio concentration (aOR 1.202, CI95% [1.061, 1.363], p = 0.004) and ? (max) CRP (aOR 1.139, CI95% [1.039, 1.248], p = 0.006), during the first 6 days of mechanical ventilation, were all significantly associated with VAP development. Both PCT and MR-proADM showed a poor predictive performance as well as temperature and white cell count. CONCLUSIONS:Our results suggest that in patients under mechanical ventilation, daily CRP monitoring was useful in VAP prediction. Trial registration NCT02078999.
Project description:BACKGROUND:To evaluate whether soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) can be used as an early predictor of ventilator-associated pneumonia (VAP). METHODS:Ventilated neonatal patients admitted into the neonatology department between January 2017 and January 2018 were divided into VAP (n?=?30) and non-VAP (n?=?30) groups. Serum sTREM, procalcitonin (PCT), C-reactive protein and interleukin-6 levels were measured at 0, 24, 72, and 120?h after initiation of mechanical ventilation (MV). Correlations between blood biomarker concentrations and VAP occurrence were analyzed. Predictive factors for VAP were identified by logistic regression analysis and Hosmer-Lemeshow test, and the predictive value of sTREM-1 and biomarker combinations for VAP was determined by receiver operating characteristic curve analysis. RESULTS:The serum sTREM-1 concentration was significantly higher in the VAP group than in the non-VAP group after 72 and 120?h of MV (72?h: 289.5 (179.6-427.0) vs 202.9 (154.8-279.6) pg/ml, P?<?0.001; 120?h: 183.9 (119.8-232.1) vs 141.3 (99.8-179.1) pg/ml, P?=?0.042). The area under the curve (AUC) for sTREM-1 at 72?h was 0.902 with a sensitivity of 90% and specificity of 77% for the optimal cut-off value of 165.05?pg/ml. Addition of PCT to sTERM-1 at 72?h further improved the predictive value, with this combination having an AUC of 0.971 (95% confidence interval: 0.938-1.000), sensitivity of 0.96, specificity of 0.88, and Youden index of 0.84. CONCLUSION:sTREM-1 is a reliable predictor of VAP in neonates, and combined measurement of serum levels of sTREM-1 and PCT after 72?h of MV provided the most accurate prediction of VAP in neonatal patients.
Project description:To determine the role of biomarkers in the clinical management of respiratory complications (RC) in hematopoietic stem cell transplantation (HSCT) recipients, we have prospectively evaluated a cohort of 175 patients followed-up for 1 year after HSCT. To avoid misinterpretation, we have excluded both unidentified respiratory infections (RI) and mixed RI. A total of 64 RC were included. Plasma levels of C-reactive protein (CRP), procalcitonin (PCT) and proadrenomedullin (proADM) were measured at diagnosis and on day 3 and 7. Different cytokines were evaluated in serum on the first day. No HSCT recipients without RC were included as a control group. Compared with RI, non-infectious RC showed a significant increase in CRP, proADM and interleukin 6 on day 0 (P=0.005; P=0.03 and P=0.04, respectively). When only RI were considered, we observed that bacterial-fungal PI showed higher levels of CRP (P=0.02), PCT (P=0.04) and proADM (P<0.01). Persistent low levels of proADM biomarkers suggest viral infection (specificity and positive predictive value 100%). Patients dying of RC had PCT and proADM levels higher than survivors (P=0.002 and P=0.03, respectively). In HSCT recipients biomarkers increase in both infectious and non-infectious RC. They may have utility in the assessment of the severity of RC and in suspecting a viral etiology.
Project description: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].
Project description:Biomarkers are widely used to confirm the presence of infection. However, it would be of the greatest importance to predict in advance the occurrence or worsening of organ dysfunction in infected patients allowing timely antibiotic escalation. This study investigates the ability of procalcitonin (PCT) and MR-proADM to predict the transition to sepsis in infected patients. The study was conducted in a neurointensive care unit over a three-month period. We included both patients with and without infection to investigate the specificity of organ dysfunction prediction in infected patients. Daily measurement of PCT and MR-proADM, SOFA, Pitt, and CPIS were performed. To measure the correlation between each biomarker and each severity score, linear mixed-effects models were developed. For each biomarker-score combination we tested the correlation of the score with the biomarker measured one and two days before, the same day, and the day after. Sixty-four critically ill patients, 31 with infection, were enrolled. The statistically significant biomarker-score combinations were PCT-SOFA, MR-proADM-SOFA, MR-proADM-Pitt, and MR-proADM-CPIS. The MR-proADM models predicting Pitt and CPIS variations with 24-hour anticipation showed the best fit. The scores increased by 0.6 ± 0.3 and 0.4 ± 0.2 for each unitary biomarker increase, respectively. The MR-proADM-SOFA combinations were equivalent when the biomarker was measured the day before or the same day (score increases were 1.5 ± 0.4 and 1.9 ± 0.4, respectively). The PCT-SOFA model had the best fit when PCT was measured the same day of the score. There was no difference in the predictive ability of the biomarker in infected and non-infected patients. This was a pivotal study conducted in a single neurointensive centre on a limited number of patients, and as such it does not provide definitive conclusions. PR-proADM predicted occurrence and worsening of organ failure in critically ill patients with and without infection. The combination with infection diagnostic biomarkers such as PCT would allow predicting evolution to sepsis in infected patients.
Project description:The aim was to provide global experts ranking on priorities in diagnostic tools for VAP in clinical practice. A multiple criteria decision analysis (MCDA) was performed to identify diagnosis tools for VAP diagnosis. Priority factors were identified after literature review. An international, multidisciplinary expert panel reviewed variables and ranked diagnostic tools. Experts from ten European hospitals participated. Regarding bedside clinical practices, seven required chest X-ray use in all patients, whereas six reported the use of blood cultures and endotracheal aspirate in all patients. Invasive techniques were routinely performed in seven sites. CRP, PCT, and Gram stains were performed in all patients by 5, 2, and 8, respectively. Impact on patient outcomes, safety, and impact on the decision to start antibiotic therapy were ranked as the top three relevant concerns (7.7/10, 7/10, and 6.9/10, respectively). Chest X-ray was ranked as the most important imaging technique to diagnose VAP (score 251.7). Apart from blood cultures, endotracheal aspirate culture was identified as the main collection method for the microbiological testing (scores of 274.8 and 246.8, respectively). Mini-BAL was the preferred invasive technique with a score of 208. Top three biomarkers were CRP (score 184.3), PCT (181.3), and WBC (166.4). Gram stain (192.5) was prioritized among laboratory diagnostic techniques. Using MCDA, it is recommended to perform a combination of diagnostic techniques including images (chest X-ray), culture of clinical specimens (blood cultures and endotracheal aspirate), and biomarkers (CRP or PCT) for VAP diagnosis at the bedside. Gram stain was ranked as the preferred laboratory technique.
Project description:OBJECTIVE:To identify potential predictors for invasive and non-invasive mechanical ventilation in coronavirus disease 2019 (COVID-19) patients. METHODS:This study retrospectively analyzes data of 516 patients with confirmed COVID-19, who were categorized into three groups based on which mechanical ventilation method was used during the hospitalization period. RESULTS:Among 516 confirmed cases with COVID-19, 446 patients did not receive mechanical ventilation, 38 patients received invasive mechanical ventilation (IMV) and 32 received non-invasive mechanical ventilation (NIMV). The median age of the included patients was 61?years old (interquartile range, 52-69). A total of 432 patients had one or more coexisting illnesses. The main clinical symptoms included fever (79.46%), dry cough (66.47%) and shortness of breath (46.90%). IMV and NIMV patients included more men, more coexisting illnesses and received more medication. Patients in the IMV group and NIMV had higher leukocyte and neutrophil count, lower lymphocyte count, higher aspartate aminotransferase (AST), lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin (PCT) and D-dimer levels and lower albumin (ALB) level. The univariate and multiple logistic regression analysis showed that the use of glucocorticoid, increased neutrophil count and LDH had a predictive role as indicators for IMV, and the use of glucocorticoid, increased neutrophil count and PCT had a predictive role as indicators for NIMV. The area under the curve (AUC) of use of glucocorticoid, increased neutrophil count and LDH was 0.885 (95% confidence interval (CI) 0.838-0.933, p?<?0.0001), which provided the specificity and sensitivity 77.7% and 90.9%, respectively. AUC of the use of glucocorticoid, increased neutrophil count and PCT for NIMV was 0.888 (95% CI 0.825-0.952, p?<?0.0001), which provided the specificity and sensitivity 70.3% and 96.4%, respectively. CONCLUSION:Glucocorticoid, increased neutrophil and LDH were predictive indicators for IMV, whereas glucocorticoid, increased neutrophil and PCT were predictive indicators for NIMV. In addition, the above-mentioned mediators had the most predictive meaning for mechanical ventilation when combined.The reviews of this paper are available via the supplemental material section.
Project description: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.
Project description:This project was a prospective translational study aimed at evaluating gene expression profiles (GEP) of patients with ventilator-associated pneumonia (VAP) . GEP of VAP were compared with a control group of patients which did not developed ventilator-associated lower respiratory tract infection despite being subjected to mechanical ventilation.
Project description:Background:The aim of the study was to evaluate the composition and the temporal evolution of the oropharyngeal microbiome in antibiotic-naïve patients requiring mechanical ventilation and to gain new insights into the pathogenesis of ventilator-associated pneumonia (VAP). Methods:Prospective, observational single-center nested case-control study. Patients with acute critical illness and anticipated duration of mechanical ventilation > 4 days were eligible. We took oropharyngeal swabs (and if available, tracheal secretions) daily, starting at the day of intubation. The microbiota was characterized by 16S rRNA high-throughput sequencing and compared between patients developing VAP versus controls. Results:Five patients developed VAP. In three patient the causative pathogens were Enterobacteriaceae and in two Haemophilus influenzae. Locally weighted polynomial regression suggested that the within diversity (=alpha) was lower in Enterobacteriaceae VAP patients between days two to five of mechanical ventilation when compared to controls. Detection of Enterobacteriaceae in the oropharynx occurred on day two of follow-up and consisted of a single operational taxonomic unit in 2/3 patients with enterobacterial VAP. Conclusions:In acutely-ill patients who developed enterobacterial VAP the causative pathogen gained access to the oropharynx early after starting mechanical ventilation and outgrew the commensal members of the microbiome. Whether a specific pattern of the oropharyngeal microbiome between days three to five of mechanical ventilation may predict VAP enterobacterial VAP has to be evaluated in further studies.
Project description: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.