Can Biomarkers Correctly Predict Ventilator-associated Pneumonia in Patients Treated With Targeted Temperature Management After Cardiac Arrest? An Exploratory Study of the Multicenter Randomized Antibiotic (ANTHARTIC) Study.

IMPORTANCE: Ventilator-associated pneumonia (VAP) frequently occurs in patients with cardiac arrest. Diagnosis of VAP after cardiac arrest remains challenging, while the use of current biomarkers such as C-reactive protein (CRP) or procalcitonin (PCT) is debated. OBJECTIVES: To evaluate biomarkers' impact in helping VAP diagnosis after cardiac arrest. DESIGN SETTING AND PARTICIPANTS: This is a prospective ancillary study of the randomized, multicenter, double-blind placebo-controlled ANtibiotherapy during Therapeutic HypothermiA to pRevenT Infectious Complications (ANTHARTIC) trial evaluating the impact of antibiotic prophylaxis to prevent VAP in out-of-hospital patients with cardiac arrest secondary to shockable rhythm and treated with therapeutic hypothermia. An adjudication committee blindly evaluated VAP according to predefined clinical, radiologic, and microbiological criteria. All patients with available biomarker(s), sample(s), and consent approval were included. MAIN OUTCOMES AND MEASURES: The main endpoint was to evaluate the ability of biomarkers to correctly diagnose and predict VAP within 48 hours after sampling. The secondary endpoint was to study the combination of two biomarkers in discriminating VAP. Blood samples were collected at baseline on day 3. Routine and exploratory panel of inflammatory biomarkers measurements were blindly performed. Analyses were adjusted on the randomization group. RESULTS: Among 161 patients of the ANTHARTIC trial with available biological sample(s), patients with VAP (n = 33) had higher body mass index and Acute Physiology and Chronic Health Evaluation II score, more unwitnessed cardiac arrest, more catecholamines, and experienced more prolonged therapeutic hypothermia duration than patients without VAP (n = 121). In univariate analyses, biomarkers significantly associated with VAP and showing an area under the curve (AUC) greater than 0.70 were CRP (AUC = 0.76), interleukin (IL) 17A and 17C (IL17C) (0.74), macrophage colony-stimulating factor 1 (0.73), PCT (0.72), and vascular endothelial growth factor A (VEGF-A) (0.71). Multivariate analysis combining novel biomarkers revealed several pairs with p value of less than 0.001 and odds ratio greater than 1: VEGF-A + IL12 subunit beta (IL12B), Fms-related tyrosine kinase 3 ligands (Flt3L) + C-C chemokine 20 (CCL20), Flt3L + IL17A, Flt3L + IL6, STAM-binding protein (STAMBP) + CCL20, STAMBP + IL6, CCL20 + 4EBP1, CCL20 + caspase-8 (CASP8), IL6 + 4EBP1, and IL6 + CASP8. Best AUCs were observed for CRP + IL6 (0.79), CRP + CCL20 (0.78), CRP + IL17A, and CRP + IL17C. CONCLUSIONS AND RELEVANCE: Our exploratory study shows that specific biomarkers, especially CRP combined with IL6, could help to better diagnose or predict early VAP occurrence in cardiac arrest patients.

Association between lactate dehydrogenase and ventilator-associated pneumonia risk: an analysis of the MIMIC database 2001-2019.

BACKGROUND: Serum lactate dehydrogenase (LDH) is a nonspecific inflammatory biomarker and has been reported to be associated with pneumonia prognosis. This study aimed to evaluate the relationship between LDH levels and ventilator-associated pneumonia (VAP) risk in intensive care unit (ICU) patients. METHODS: This retrospective cohort study used data from the Multiparameter Intelligent Monitoring in Intensive Care database from 2001 to 2019. ICU patients aged ≥ 18 years and receiving mechanical ventilation were included. LDH levels were analyzed as continuous and categorical variables (< 210, 210-279, 279-390, > 390 IU/L), respectively. Restricted cubic spline (RCS) curves and quartiles were used to categorize LDH levels. Logistic regression and linear regression were utilized to assess the relationship of LDH levels with VAP risk and duration of mechanical ventilation, respectively. RESULTS: A total of 9,164 patients were enrolled, of which 646 (7.05%) patients developed VAP. High levels of LDH increased the risk of VAP [odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.06-1.24] and LDH levels were positively correlated with the duration of mechanical ventilation [ß = 4.49, 95%CI: (3.42, 5.56)]. Moreover, patients with LDH levels of 279-390 IU/L (OR = 1.38, 95%CI: 1.08-1.76) and > 390 IU/L (OR = 1.50, 95%CI: 1.18-1.90) had a higher risk of VAP than patients with LDH levels < 210 IU/L. Patients with LDH levels of 279-390 IU/L [ß = 3.84, 95%CI: (0.86, 6.82)] and > 390 IU/L [ß = 11.22, 95%CI: (8.21, 14.22)] (vs. <210 IU/L) had a longer duration of mechanical ventilation. CONCLUSION: Elevated serum LDH levels were related to a higher risk of VAP and longer duration of mechanical ventilation and may be useful for monitoring VAP risk.

Lipoprotein concentrations over time in the intensive care unit COVID-19 patients: Results from the ApoCOVID study.

INTRODUCTION: Severe acute respiratory syndrome coronavirus2 has caused a global pandemic of coronavirus disease 2019 (COVID-19). High-density lipoproteins (HDLs), particles chiefly known for their reverse cholesterol transport function, also display pleiotropic properties, including anti-inflammatory or antioxidant functions. HDLs and low-density lipoproteins (LDLs) can neutralize lipopolysaccharides and increase bacterial clearance. HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) decrease during bacterial sepsis, and an association has been reported between low lipoprotein levels and poor patient outcomes. The goal of this study was to characterize the lipoprotein profiles of severe ICU patients hospitalized for COVID-19 pneumonia and to assess their changes during bacterial ventilator-associated pneumonia (VAP) superinfection. METHODS: A prospective study was conducted in a university hospital ICU. All consecutive patients admitted for COVID-19 pneumonia were included. Lipoprotein levels were assessed at admission and daily thereafter. The assessed outcomes were survival at 28 days and the incidence of VAP. RESULTS: A total of 48 patients were included. Upon admission, lipoprotein concentrations were low, typically under the reference values ([HDL-C] = 0.7[0.5-0.9] mmol/L; [LDL-C] = 1.8[1.3-2.3] mmol/L). A statistically significant increase in HDL-C and LDL-C over time during the ICU stay was found. There was no relationship between HDL-C and LDL-C concentrations and mortality on day 28 (log-rank p = 0.554 and p = 0.083, respectively). A comparison of alive and dead patients on day 28 did not reveal any differences in HDL-C and LDL-C concentrations over time. Bacterial VAP was frequent (64%). An association was observed between HDL-C and LDL-C concentrations on the day of the first VAP diagnosis and mortality ([HDL-C] = 0.6[0.5-0.9] mmol/L in survivors vs. [HDL-C] = 0.5[0.3-0.6] mmol/L in nonsurvivors, p = 0.036; [LDL-C] = 2.2[1.9-3.0] mmol/L in survivors vs. [LDL-C] = 1.3[0.9-2.0] mmol/L in nonsurvivors, p = 0.006). CONCLUSION: HDL-C and LDL-C concentrations upon ICU admission are low in severe COVID-19 pneumonia patients but are not associated with poor outcomes. However, low lipoprotein concentrations in the case of bacterial superinfection during ICU hospitalization are associated with mortality, which reinforces the potential role of these particles during bacterial sepsis.

Significance of sTREM-1 in early prediction of ventilator-associated pneumonia in neonates: a single-center, prospective, observational study.

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.

The predictive value of procalcitonin in ventilator-associated pneumonia after cardiac valve replacement.

This study aimed to evaluate the predictive value of procalcitonin (PCT) in ventilator-associated pneumonia (VAP) after cardiac valve replacement. A total of 80 patients who underwent cardiac valve replacement in our department were enrolled in this study. Of these patients,40 were diagnosed with VAP and assigned to the observation group, while the other 40 patients not diagnosed with VAP were assigned to the control group. The changes in serum PCT, white blood cell count and C-reactive protein (CRP) were observed before each operation (T0), on the first day after the operation (T1), the second day after the operation (T2) and the third day after the operation (T3). After the operation, the serum PCT in the observation group was significantly higher than those at different time points after the operation, and also significantly higher than those in the control group (p < .05). In the control group, PCT was significantly higher after the operation than before the operation (p < .05), but the differences among the different postoperative time points were not statistically significant (p > .05). In the two groups, the white blood cell count and CRP were significantly higher after the operation than before the operation (p < .05), but the differences between the two groups were not statistically significant (p > .05). Serum PCT is an early, sensitive and highly specific high-risk monitoring index and has an early prediction value for VAP after cardiac valve replacement.

Assessment of ventilator-associated pneumonia by combining 8-isoprostane and nitric oxide levels in exhaled breath condensate with the clinical pulmonary infection score.

OBJECTIVE: To investigate the effectiveness of combining the 8-isoprostane and nitric oxide (NO) levels in exhaled breath condensate (EBC) with the clinical pulmonary infection score (CPIS) to assess ventilator-associated pneumonia (VAP) in patients on mechanical ventilation. METHODS: Thirty-two patients with VAP served as the observation group and 32 patients without VAP served as the control group. The correlations of 8-isoprostane and NO levels in EBC with CPIS, chest X-ray score, oxygenation index, and lung injury score (LIS) were analyzed. The area under the curve (AUC) was compared with experimental data using the receiver operating characteristic curve (ROC) to predict VAP. RESULTS: The 8-isoprostane and NO levels in EBC of VAP patients on mechanical ventilation were positively correlated with CPIS, chest X-ray score, and LIS, but negatively correlated with oxygenation index. The AUC of simplified CPIS combined with 8-isoprostane and NO levels in EBC for predicting VAP was 0.914, which suggests that this is a highly effective for making a diagnosis. CONCLUSIONS: The simplified CPIS combined with the 8-isoprostane and NO levels in EBC of patients on mechanical ventilation is effective for evaluating and diagnosing VAP. 8-Isoprostane and NO levels in EBC could be used as biomarkers to evaluate VAP.

Diagnostic value of pentraxin 3 in respiratory tract infections: A meta-analysis.

BACKGROUND: Pentraxin 3 is an acute inflammatory protein of the long pentraxin subfamily. A meta-analysis was performed to assess diagnostic accuracy of pentraxin 3 for respiratory tract infections. METHODS: We identify studies examining diagnostic value of pentraxin 3 for respiratory tract infections by searching Pubmed, Web of Knowledge, and Cochrane Library. The sensitivity, specificity, negative likelihood ratio (LR), positive LR, and diagnostic odds ratio were pooled. The area under the summary receiver operator characteristic (SROC) curve and Q point value (Q*) were calculated. RESULTS: A total of 8 studies with 961 individuals were eligible for this meta-analysis. The pooled sensitivity of pentraxin 3 in diagnosis of respiratory tract infections was 0.78, the pooled specificity was 0.73, the area under the SROC curve was 0.84, and the Q* was 0.77. The area under the SROC curve of serum and bronchoalveolar lavage fluid (BALF) pentraxin 3 was 0.85 and 0.89, respectively. Meta-regression analysis revealed that cutoff value was the source of heterogeneity among the included studies. The Deek funnel plot test suggested no evidence of publication bias. Subgroup analyses showed that the area under the SROC curve of pentraxin 3 in diagnosis of ventilator-associated pneumonia (VAP) was 0.89. CONCLUSION: Pentraxin 3 has a moderate accuracy for diagnosing respiratory tract infections and VAP. The overall diagnostic value of BALF level of pentraxin 3 is superior to its serum concentration.

Monocyte Chemoattractant Protein-1, a Possible Biomarker of Multiorgan Failure and Mortality in Ventilator-Associated Pneumonia.

Ventilator-associated pneumonia (VAP) leads to increased patients' mortality and medical expenditure. Monocyte chemoattractant protein-1 (MCP-1) plays a role in the pathogenesis of lung inflammation and infection. Therefore, the plasma concentration of MCP-1 was assessed and correlated with the clinical course in VAP patients. This retrospective observational study recruited 45 healthy volunteers, 12 non-VAP subjects, and 30 VAP patients. The diagnostic criteria for VAP were based on the American Thoracic Society guidelines, and the level of plasma MCP-1 was determined by ELISA. Plasma MCP-1 concentration was significantly elevated in the acute stage in VAP patients when compared with the control (p < 0.0001) and non-VAP patient groups (p = 0.0006). Subsequently, it was remarkably decreased following antibiotic treatment. Moreover, plasma MCP-1 concentration was positively correlated with indices of pulmonary dysfunction, including the lung injury score (p = 0.02) and the oxygenation index (p = 0.02). When patients with VAP developed adult respiratory distress syndrome (ARDS), their plasma MCP-1 concentrations were significantly higher than those of patients who did not develop ARDS (p = 0.04). Moreover, plasma MCP-1 concentration was highly correlated with organ failure scores, including simplified acute physiology score II (SAPS II, p < 0.0001), sequential organ failure assessment score (SOFA, p < 0.0001), organ dysfunctions and/or infection (ODIN, p < 0.0001), predisposition, insult response and organ dysfunction (PIRO, p = 0.005), and immunodeficiency, blood pressure, multilobular infiltrates on chest radiograph, platelets and hospitalization 10 days before onset of VAP (IBMP-10, p = 0.004). Our results demonstrate that plasma MCP-1 is an excellent marker for recognizing VAP when the cut-off level is set to 347.18 ng/mL (area under the curve (AUC) = 0.936, 95% CI = 0.863-0.977). In conclusion, MCP-1 not only could be a biological marker related to pulmonary dysfunction, organ failure, and mortality in patients with VAP, but also could be used for early recognition of VAP.

Rapid genetic and phenotypic changes in Pseudomonas aeruginosa clinical strains during ventilator-associated pneumonia.

Treatment with antibiotics leads to the selection of isolates with increased resistance. We investigated if evolution towards resistance was associated with virulence changes, in the context of P. aeruginosa ventilator-associated pneumonia (VAP). Four patients were selected because they had multiple VAP episodes during short periods (12 days to 5 weeks), with emergence of resistance. We performed whole-genome sequencing of 12 P. aeruginosa from bronchoalveolar lavages or blood culture (3 isolates per patient). Production of quorum sensing-dependent virulence factors, serum resistance, cytotoxicity against A549 cells, biofilm production, and twitching motility were studied. Each patient was infected with a unique strain. For all patients, resistance development was explained by genetic events in ampD, mexR or oprD. Additional variations were detected in virulence- and/or fitness-associated genes (algB, gacA, groEL, lasR, mpl, pilE, pilM, rhlR) depending on the strain. We noticed a convergence towards quorum sensing deficiency, correlated with a decrease of pyocyanin and protease production, survival in serum, twitching motility and cytotoxicity. In one patient, changes in pilM and pilE were related to enhanced twitching. We show that the emergence of resistance in P. aeruginosa is associated with virulence modification, even in acute infections. The consequences of this short-term pathoadaptation need to be explored.

Lung Ultrasound Combined With Procalcitonin for a Diagnosis of Ventilator-Associated Pneumonia.

BACKGROUND: Lung ultrasound is a valuable imaging tool in the diagnosis of community-acquired pneumonia. However, its diagnostic accuracy in ventilator-associated pneumonia (VAP) has not been fully investigated. The aim of this study was to evaluate the diagnostic performance of the combination of a lung ultrasound with procalcitonin (PCT) in mechanically ventilated subjects with symptoms suggestive of pneumonia. METHODS: A prospective study of 124 subjects with suspected VAP in 2 multidisciplinary ICUs was conducted between December 2016 and October 2017. Lower respiratory tract specimens were collected from all the subjects at enrollment and on the following 3 d. PCT assays were performed within 1 h of enrollment. Lung ultrasound and then computed tomography of the chest were performed within 24 h to detect lung consolidations. The subjects were divided into VAP and non-VAP groups according to the results of a computed tomography of the chest and semi-quantitative culture of the lower respiratory tract sample. RESULTS: A total of 124 subjects were included (48 in the VAP group and 76 in the non-VAP group). A positive lung ultrasound result combined with PCT of ≥0.25 ng/mL diagnosed VAP, with a sensitivity and specificity of 81.3 and 85.5%, respectively. The area under the receiver operating characteristic curve was significantly higher for lung ultrasound combined with PCT than for a white blood cell count, PCT, C-reactive protein, or Clinical Pulmonary Infection Score alone. CONCLUSIONS: A combination of lung ultrasound and PCT was accurate in the diagnosis of VAP. Lung ultrasound is a useful lung-imaging tool to assist VAP diagnosis.

Diagnostic Efficacy of Serum Amyloid A Protein and Soluble Intercellular Adhesion Molecule 1 in Pediatric Ventilator-Associated Pneumonia.

OBJECTIVES: Study of inflammatory biomarkers which may aid in early detection of ventilator-associated pneumonia (VAP) in children and predicting their outcome. PATIENTS: Thirty-five children, aged 2 months to 13 years, needed mechanical ventilation (MV) for more than 48 hours due to causes other than pneumonia. METHODS: Measurement of serum amyloid A (SAA) protein, soluble intercellular adhesion molecule 1 (sICAM-1), and C-reactive protein (CRP), modified clinical pulmonary infection score (CPIS) and performing culture of endotracheal aspirate at the start and on the third day of MV. RESULTS: Ventilator-associated pneumonia was diagnosed by CPIS in 6 (17.1%) of 35 patients. On the third day of MV, there was a significant increase in serum mean levels of SAA, sICAM-1, and CRP in comparison to the start of MV ( P = .005, .004, and .01, respectively). Three (50%) of 6 patients with VAP died, while 4 (14.28%) of 28 patients without VAP died. The sensitivity of serum SAA, sICAM-1, and CPIS were 100% for predicting VAP, while specificity was highest for CPIS (96.55%) followed by SAA (93.1%). Combination of CPIS and SAA increased the specificity to 100%. For predicting nonsurvival, serum SAA and sICAM-1 had a sensitivity of 100% and a specificity of 92.86% and 89.29%, respectively. CONCLUSION: Serum amyloid A and sICAM-1 may be considered as reliable markers for detection of VAP. Combination of serum SAA with CPIS increased the specificity to 100%. Measurement of SAA in patients with VAP also had a good predictive value for nonsurvival in such patients.

Diagnostic value of procalcitonin in ventilator-associated pneumonia. / Valor diagnóstico de la procalcitonina en la neumonía asociada a ventilación mecánica.

BACKGROUND AND OBJECTIVE: Procalcitonin (PCT) can help the early diagnosis of bacterial infections and estimate the response obtained. The objective is to study the value of PCT for the diagnosis of ventilator-associated pneumonia (VAP). PATIENTS AND METHOD: Prospective and observational study, carried out for 18 months, in a polyvalent Intensive Care Unit (ICU). Those included were over 18 years of age, with suspected pneumonia after 48h of mechanical ventilation (MV). Collected were demographic characteristics; admission pathology; reason for beginning MV; gravity scores (APACHE II, SAPS II and SOFA); C-reactive protein (CRP) and PCT. At the time of suspicion of VAP: early or late, radiological severity, presence of septic shock, SOFA, CRP, PCT and microbiology. RESULTS: Ninety-one patients with suspected VAP were included. The mean age was 42 (17.76) and that of hospitalisation in the ICU was 18.59 (11.69) days. VAP was confirmed in 74 patients, of which 19 (25.7%) presented septic shock. The mortality was 28.4%. There were no significant differences of the PCT in the patients who presented VAP versus those who did not present VAP (P=.449). When patients without VAP, with VAP and VAP with shock, were compared, the PCT median was 0.38 (CI95%: 0.22-1.90), 0.56 (CI95%: 0.19-1.77) and 1.93 (CI95%: 0.38-10.07), respectively (P=.169). CONCLUSIONS: In our study, PCT did not prove useful for the diagnosis of VAP.

Serum vitamin D level was not associated with severity of ventilator associated pneumonia.

BACKGROUND AND OBJECTIVE: Vitamin D deficiency is considered one of the most common nutritional deficiencies associated with weakened immune system and increased likelihood of sepsis. The current study was conducted to investigate the association between serum vitamin D level and the severity and prognosis of ventilator associated pneumonia (VAP) in inpatients in intensive care unit (ICU). METHODS: Eighty-four consecutive patients with VAP were enrolled in this observational, prospective study conducted in the ICU of Besat Hospital, Hamadan. The patients were examined for serum 25-hydroxyvitamin D (vitD3) level and VAP severity and prognosis. Clinical pulmonary infection score was used for the diagnosis, and Sequential Organ Failure Assessment (SOFA) Score was used to determine the severity of VAP. RESULTS: Low level serum vitD3 (under 30 ng/mL) was found in 66 (78.6%) patients. In this series of VAP patients, there were no significant differences in blood culture results, 14 and 28-day sepsis-associated mortality, mechanical ventilation duration, or SOFA Score on days 3, 7, and 14 between the low level and normal level vitD3 patients (p > 0.05). CONCLUSION: Serum vitD3 level was not associated with mortality from VAP or complications due to sepsis in the inpatients in the ICU.

Can endocan be a new biomarker in ventilator-associated pneumonia?

Ventilator-Associated Pneumonia (VAP) is a hospital-acquired bacterial infection with high incidence and mortality rate. The aim of this study is to investigate the correlation between the Endocan level and development of VAP and whether or not this correlation was correlated with the clinical findings. Demographic data, white blood cell (WBC) count, procalcitonin (PCT), c-reactive protein (CRP), and fever levels of 60 patients were recorded in serial measurements for 5 days. When there was the presence of fever or elevated Endocan, alveolar lavage culture was taken and chest radiographies were taken. Correlations of the Endocan levels with the culture results and laboratory values were examined. The rate of VAP was found as 10.4/1000 mechanical ventilator days. Endocan levels were significantly higher in patients with VAP (p < 0.05). However, there was no significant difference among PCT, WBC, CRP measurements (p > 0.05). No correlation was found between Endocan levels and PCT, WBC and CRP levels in those with VAP (p > 0.05). A significant correlation was found between the Endocan level and the elevated fever 24 h later (p:0.001). The serum Endocan level on the day 3 had a specificity of 73.3%, a sensitivity of 68.9%, positive predictive value of 44%, and negative predictive value of 88.5% at the cut off level of 9.17 ng/mL. In this study, it was determined that high Endocan levels were associated with the development of VAP. The present study suggested that Endocan can be used as a screening tool for the development of VAP. CLINICAL TRIALS.GOV ID: NCT02916277.

A novel biomarker of serum Histidine-Rich Glycoprotein (HRG) for diagnosing and predicting prognosis of ventilator-associated pneumonia (VAP): a pilot study.

OBJECTIVE: Histidine-Rich Glycoprotein (HRG) has been reported to be associated with idiopathic pulmonary fibrosis, cancer, and sepsis as a novel biomarker. However, there is limited evidence regarding its value in diagnosing or prognosis evaluating of ventilator-associated pneumonia (VAP). PATIENTS AND METHODS: A total of 186 patients intubated in ICU and 65 healthy volunteers were enrolled in this study. Patients were divided into VAP group (n = 116), non-VAP group (n = 70) and control group (n = 65). The HRG, C reactive protein (CRP) and procalcitonin (PCT) levels were measured 72 hours after intubation, while blood sample was acquired from healthy controls for the test. RESULTS: HRG of VAP group was significantly lower than non-VAP group and control group (p < 0.001), while CRP and PCT were significantly higher (p < 0.001). The ROC analysis showed that the AUC of HRG was 0.777 95% CI (0.708-0.847) with a cut-off value of 38.55 µg/mL, which was lower than CRP [AUC = 0.912, 95% CI (0.847-0.950)] and PCT [AUC = 0.818, 95% CI (0.759-0.876)]. No linear correlation was found between HRG and CRP, as well as PCT (p > 0.05). However, the survival analysis showed that patients with higher level of HRG had a significantly higher survival rate (p < 0.001). The multivariate Cox regression analysis also demonstrated that the higher level of HRG was associated with better survival [HR 0.290, 95% CI (0.131-0.641), p = 0.002]. CONCLUSIONS: Serum HRG decreases when the patient develops VAP, which might be used as a biomarker for the diagnosis of VAP, with relatively less accuracy than PCT and CRP. However, HRG is valuable in predicting the clinical outcomes of mechanical ventilation patients.

Diagnostic efficacy of serum procalcitonin, C-reactive protein concentration and clinical pulmonary infection score in Ventilator-Associated Pneumonia.

OBJECTIVE: The aim of this study was to evaluate the diagnostic efficacy of serum procalcitonin (PCT), c-reactive protein (CRP) concentration and clinical pulmonary infection score(CPIS) in ventilator-associated pneumonia(VAP). METHODS: Forty-nine patients who were admitted to the intensive care unit (ICU) of Zhejiang Hospital with suspected VAP were recruited in this study. The serum level of PCT and CRP of all patients were measured and CPIS was calculated at the time of VAP suspected diagnosis. Of the included 49 patients, 24 were finally confirmed of VAP by microbiology assay. And the other 25 patients were considered as clinical suspected VAP without microbiology confirmation. The diagnostic sensitivity, specificity and area under the receiver operating characteristic (ROC) curve (AUC) were calculated using the serum PCT, CRP concentration and CPIS. The correlation among serum PCT, CRP concentration and CPIS were also evaluated by Spearson correlation test. RESULTS: A total of 100 bronchoscopic aspiration sputum specimen were examined in bacterial culture. 30 samples were found with suspected pathogenic bacteria. Six samples were found with 2 types of suspected pathogenic bacteria. PCT serum concentration and CPIS score were significantly different (P<0.05) between the patient group [1.4 (0.68 ∼ 2.24), 6.0 (4.25 ∼ 8.00)] and the control group [0.4 (0.17 ∼ 1.39), 3.0 (1.00 ∼ 5.00)] ; However, the serum CRP [102.8(66.75 ∼ 130.90) vs 86.1(66.95 ∼ 110.10)] was not statistically different between the two groups (P>0.05). A significant correlation was found between serum PCT and CRP concentrations (r=0.55, P<0.01), but not between PCT vs CPIS and CRP vs CPIS (p>0.05). The diagnostic sensitivity, specificity and AUC were 72.0%, 75.0%, 0.81 (0.69 ∼ 0.93) for CPIS; 60.0%, 87.5%, 0.76 (0.62 ∼ 0.90) for PCT and 68.0%, 58.3%, 0.59 (0.43 ∼ 0.76) for CRP. CONCLUSION: PCT serum level and CPIS score are elevated in VAP patients and could therefore represent potential biomarkers for VAP early diagnosis.

Profiling inflammatory markers in patients with pneumonia on intensive care.

Clinical investigations lack predictive value when diagnosing pneumonia, especially when patients are ventilated and develop ventilator associated pneumonia (VAP). New tools to aid diagnosis are important to improve outcomes. This pilot study examines the potential for a panel of inflammatory mediators to aid in the diagnosis. Forty-four ventilated patients, 17 with pneumonia and 27 with brain injuries, eight of whom developed VAP, were recruited. 51 inflammatory mediators, including cytokines and oxylipins, were measured in patients' serum using flow cytometry and mass spectrometry. The mediators could separate patients admitted to ICU with pneumonia compared to brain injury with an area under the receiver operating characteristic curve (AUROC) 0.75 (0.61-0.90). Changes in inflammatory mediators were similar in both groups over the course of ICU stay with 5,6-dihydroxyeicosatrienoic and 8,9-dihydroxyeicosatrienoic acids increasing over time and interleukin-6 decreasing. However, brain injured patients who developed VAP maintained inflammatory profiles similar to those at admission. A multivariate model containing 5,6-dihydroxyeicosatrienoic acid, 8,9-dihydroxyeicosatrienoic acid, intercellular adhesion molecule-1, interleukin-6, and interleukin-8, could differentiate patients with VAP from brain injured patients without infection (AUROC 0.94 (0.80-1.00)). The use of a selected group of markers showed promise to aid the diagnosis of VAP especially when combined with clinical data.

C-reactive protein and procalcitonin profile in ventilator-associated lower respiratory infections.

PURPOSE: Ventilator-associated tracheobronchitis (VAT) has been suggested as an intermediate process between tracheobronchial colonization and ventilator-associated pneumonia (VAP) in patients receiving mechanical ventilation. The aim of this study was to evaluate the ability of C-reactive protein (CRP) and procalcitonin (PCT) to differentiate between VAT and VAP. METHODS: Pre-planned analysis of the prospective multinational TAVeM database, performed on 2960 patients receiving mechanical ventilation for >48 h, including 689 patients with VA-LRTI. Patients with the diagnosis of VAT or VAP microbiologically documented and with one measurement of CRP and/or PCT on the day of diagnosis were included. RESULTS: Four hundred and four patients (mean age 63 years, 298 men, ICU mortality 40%) were studied, 207 with VAT and 197 with VAP. On the day of infection diagnosis, the median CRP was elevated in both groups but significantly higher in VAP (18 mg/dL vs. 14 mg/dL, p = .001). Median PCT was also significantly higher in VAP (2.1 ng/dL vs. 0.64 ng/d L, p < .001). Both biomarkers could not help distinguish between VAT and VAP. CONCLUSION: Although PCT and CRP presented lower values in VAT as compared to VAP, there was a marked overlap of both biomarkers values in both VA-LRTI not allowing adequate discrimination.

Do we need biomarkers for the follow-up and shortening of antibiotic treatment duration?

PURPOSE OF REVIEW: Clinical and laboratory parameters are useful tools for the diagnosis, follow-up and evaluation of resolution, and to predict outcomes when measured at different time-points onset and serially during follow-up in patients with hospital-acquired pneumonia and/or ventilator-associated pneumonia (HAP/VAP). RECENT FINDINGS: Both, the 2017 ERS/ESICM/ESCMID/Asociación Latino Americana de Tórax (EEEAG) and the 2016 IDSA/ATS guidelines (IAG) for the management of HAP/VAP recommend using clinical criteria alone, rather than biomarkers for diagnosis. Several studies were conducted to assess the value of serum biomarker concentration and kinetics for predicting the outcome in HAP/VAP, including C-reactive protein and procalcitonin (PCT). Although the EEEAG do not recommend routinely performing biomarker determinations in addition to bedside clinical assessment in patients receiving antibiotic treatment for VAP or HAP to predict adverse outcomes and clinical response, the IAG recommend that routine bedside clinical assessment should be accompanied by measurements of PCT to guide antimicrobial therapy. Additionally, the 2016 Surviving Sepsis Campaign also suggests that PCT levels can be used to support the shortening of antibiotic therapy. SUMMARY: Current evidence indicate that there is no recommendation to use biomarkers systematically to guide every decision. However, in some circumstances they might add some relevant information to our everyday practice.

Early increase of VEGF-A is associated with resolution of ventilator-associated pneumonia: Clinical and experimental evidence.

BACKGROUND AND OBJECTIVE: The role of vascular endothelial growth factor (VEGF)-A in the resolution of ventilator-associated pneumonia (VAP) was investigated in clinical and mouse pneumonia models. METHODS: VEGF-A was measured for seven consecutive days by an immunosorbent assay in sera of 82 patients with VAP and changes from baseline were correlated with the resolution of VAP. Experimental animals were challenged intratracheally with Pseudomonas aeruginosa. Mouse bronchoalveolar lavage (BAL) samples and segments of lung tissue were obtained at 24, 48 and 124 h after bacterial challenge. Levels of VEGF-A, tumour Necrosis Factor alpha (TNF-α), interleukin (IL)-1ß, interferon-gamma (IFNγ) and myeloperoxidase (MPO) activity were measured in these samples. RESULTS: VAP resolved in 36.1% of patients with a less than 45% increase of VEGF-A on day 5 compared to 65.2% of patients with a more than 45% increase (P = 0.014). This was also accompanied by an earlier resolution of VAP (log-rank: 7.99; P = 0.005) and it was not pathogen-specific. The increase of VEGF-A was an independent variable associated with VAP resolution in forward logistic regression analysis where Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were included as independent variables. VEGF-A in mouse BAL and lung tissue increased significantly at 124 h but not with the other mediators. In mice pre-treated with bevacizumab, VEGF-A concentrations decreased while TNF-α and MPO significantly increased. CONCLUSION: In patients, an association between increased levels of circulating VEGF-A and VAP resolution was observed. The mouse study suggests that elevated VEGF-A levels may be associated with lung inflammation resolution. CLINICAL TRIAL REGISTRATION: NCT00297674 at www.clinicaltrials.gov.