Kinetics of inflammatory biomarkers to predict one-year mortality in older patients hospitalized for pneumonia: a multivariable analysis.

OBJECTIVES: Long-term mortality is increased in older patients with pneumonia. We aimed to test whether residual inflammation is predictive of one-year mortality after pneumonia. METHODS: Inflammation biomarkers (C-reactive protein [CRP], interleukin [IL]-6 and IL-8, tumor necrosis factor-α, serum amyloid A, neopterin, myeloperoxidase, anti-apolipoprotein A-1, and anti-phosphorylcholine IgM) were measured at admission and discharge in older patients hospitalized for pneumonia in a prospective study. Univariate and multivariate analyses were conducted using absolute level at discharge and relative and absolute differences between admission and discharge for all biomarkers, along with usual prognostic factors. RESULTS: In the 133 included patients (median age, 83 years [interquartile range: 78-89]), one-year mortality was 26%. In univariate analysis, the relative difference of CRP levels had the highest area under the receiver operating characteristic curve (0.70; 95% confidence interval [CI] 0.60-0.80). A decrease of CRP levels of more than 67% between admission and discharge had 68% sensitivity and 68% specificity to predict survival. In multivariate analysis, lower body mass index (hazard ratio=0.87 [CI 95% 0.79-0.96], P-value=0.01), higher IL-8 (hazard ratio=1.02 [CI 95% 1.00-1.04], P-value=0.02), and higher CRP (1.01 [95% CI 1.00-1.02], P=0.01) at discharge were independently associated with mortality. CONCLUSION: Higher IL-8 and CRP levels at discharge were independently associated with one-year mortality. The relative CRP difference during hospitalization was the best individual biomarker for predicting one-year mortality.

Potential of heart fatty-acid binding protein, neurofilament light, interleukin-10 and S100 calcium-binding protein B in the acute diagnostics and severity assessment of traumatic brain injury.

BACKGROUND: There is substantial interest in blood biomarkers as fast and objective diagnostic tools for traumatic brain injury (TBI) in the acute setting. METHODS: Adult patients (≥18) with TBI of any severity and indications for CT scanning and orthopaedic injury controls were prospectively recruited during 2011-2013 at Turku University Hospital, Finland. The severity of TBI was classified with GCS: GCS 13-15 was classified as mild (mTBI); GCS 9-12 as moderate (moTBI) and GCS 3-8 as severe (sTBI). Serum samples were collected within 24 hours of admission and biomarker levels analysed with high-performance kits. The ability of biomarkers to distinguish between severity of TBI and CT-positive and CT-negative patients was assessed. RESULTS: Among 189 patients recruited, neurofilament light (NF-L) was obtained from 175 patients with TBI and 40 controls. S100 calcium-binding protein B (S100B), heart fatty-acid binding protein (H-FABP) and interleukin-10 (IL-10) were analysed for 184 patients with TBI and 39 controls. There were statistically significant differences between levels of all biomarkers between the severity classes, but none of the biomarkers distinguished patients with moTBI from patients with sTBI. Patients with mTBI discharged from the ED had lower levels of IL-10 (0.26, IQR=0.21, 0.39 pg/mL), H-FABP (4.15, IQR=2.72, 5.83 ng/mL) and NF-L (8.6, IQR=6.35, 15.98 pg/mL) compared with those admitted to the neurosurgical ward, IL-10 (0.55, IQR=0.31, 1.42 pg/mL), H-FABP (6.022, IQR=4.19, 20.72 ng/mL) and NF-L (13.95, IQR=8.33, 19.93 pg/mL). We observed higher levels of H-FABP and NF-L in older patients with mTBI. None of the biomarkers or their combinations was able to distinguish CT-positive (n=36) or CT-negative (n=58) patients with mTBI from controls. CONCLUSIONS: S100B, H-FABP, NF-L and IL-10 levels in patients with mTBI were significantly lower than in patients with moTBI and sTBI but alone or in combination, were unable to distinguish patients with mTBI from orthopaedic controls. This suggests these biomarkers cannot be used alone to diagnose mTBI in trauma patients in the acute setting.

Blood Biomarkers to Differentiate Ischemic and Hemorrhagic Strokes.

OBJECTIVE: To validate a panel of blood biomarkers to differentiate between ischemic stroke (IS) and intracerebral hemorrhage (ICH) in patients with suspected stroke. METHODS: Patients with suspected stroke admitted within 4.5 hours after onset were enrolled. Blood samples were collected at hospital admission. Glial fibrillary acid protein (GFAP), retinol binding protein 4 (RBP-4), N-terminal proB-type natriuretic peptide (NT-proBNP), and endostatin were measured by immunoassays. Cutoff points were obtained for 100% specificity for IS. A high-sensitivity assay to measure GFAP and rapid point-of-care tests (POCTs) to measure RBP-4 and NT-proBNP were used in subsets of patients. Biomarker panels were evaluated in another cohort of 62 stroke mimics. RESULTS: A total of 189 patients (154 IS and 35 ICH) were enrolled. Patients with IS had higher RBP-4, NT-proBNP, and endostatin and lower GFAP levels than patients with ICH. The best biomarker combination for the identification of IS was RBP-4+NT-proBNP, which was able to identify 29.7% of patients with IS with 100% specificity. In the subset of patients for whom GFAP was measured with the high-sensitivity assay, RBP-4, NT-proBNP, and GFAP identified 51.5% of patients with IS with 100% specificity. When stroke mimics were included, specificities were reduced to 98.4 and 96.8%, respectively. POCTs of RBP-4 and NT-proBNP showed results similar results to those of conventional ELISAs. CONCLUSIONS: A biomarker panel including RBP-4, NT-proBNP, and GFAP provided moderate but potentially useful sensitivity rates at 100% specificity for IS diagnosis. If confirmed in future studies, this strategy might allow prehospital treatment in selected patients. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that a biomarker panel including RBP-4, NT-proBNP, and GFAP distinguishes IS from ICH with moderate accuracy.

Role of Clinical Characteristics and Biomarkers at Admission to Predict One-Year Mortality in Elderly Patients with Pneumonia.

BACKGROUND: A hospitalization for community-acquired pneumonia results in a decrease in long-term survival in elderly patients. We assessed biomarkers at admission to predict one-year mortality in a cohort of elderly patients with pneumonia. METHODS: A prospective observational study included patients >65 years hospitalized with pneumonia. Assessment of PSI, CURB-65, and biomarkers (C-reactive protein (CRP), procalcitonin (PCT), NT-pro-B-type natriuretic peptide (NT-proBNP), interleukin (IL)-6 and -8, tumor necrosis factor alpha (TNF-α), serum amyloid A (SAA), neopterin (NP), myeloperoxidase (MPO), anti-apolipoprotein A-1 IgG (anti-apoA-1), and anti-phosphorylcholine IgM (anti-PC IgM)) was used to calculate prognostic values for one-year mortality using ROC curve analyses. Post hoc optimal cutoffs with corresponding sensitivity (SE) and specificity (SP) were determined using the Youden index. RESULTS: A total of 133 patients were included (median age 83 years [IQR: 78-89]). Age, dementia, BMI, NT-proBNP (AUROC 0.65 (95% CI: 0.55-0.77)), and IL-8 (AUROC 0.66 (95% CI: 0.56-0.75)) were significantly associated with mortality, with NT-proBNP (HR 1.01 (95% CI 1.00-1.02) and BMI (HR 0.92 (95% CI 0.85-1.000) being independent of age, gender, comorbidities, and PSI with Cox regression. At the cutoff value of 2200 ng/L, NT-proBNP had 67% sensitivity and 70% specificity. PSI and CURB-65 were not associated with mortality. CONCLUSIONS: NT-proBNP levels upon admission and BMI displayed the highest prognostic accuracy for one-year mortality and may help clinicians to identify patients with poor long-term prognosis.

Admission Levels of Interleukin 10 and Amyloid ß 1-40 Improve the Outcome Prediction Performance of the Helsinki Computed Tomography Score in Traumatic Brain Injury.

Background: Blood biomarkers may enhance outcome prediction performance of head computed tomography scores in traumatic brain injury (TBI). Objective: To investigate whether admission levels of eight different protein biomarkers can improve the outcome prediction performance of the Helsinki computed tomography score (HCTS) without clinical covariates in TBI. Materials and methods: Eighty-two patients with computed tomography positive TBIs were included in this study. Plasma levels of ß-amyloid isoforms 1-40 (Aß40) and 1-42 (Aß42), glial fibrillary acidic protein, heart fatty acid-binding protein, interleukin 10 (IL-10), neurofilament light, S100 calcium-binding protein B, and total tau were measured within 24 h from admission. The patients were divided into favorable (Glasgow Outcome Scale-Extended 5-8, n = 49) and unfavorable (Glasgow Outcome Scale-Extended 1-4, n = 33) groups. The outcome was assessed 6-12 months after injury. An optimal predictive panel was investigated with the sensitivity set at 90-100%. Results: The HCTS alone yielded a sensitivity of 97.0% (95% CI: 90.9-100) and specificity of 22.4% (95% CI: 10.2-32.7) and partial area under the curve of the receiver operating characteristic of 2.5% (95% CI: 1.1-4.7), in discriminating patients with favorable and unfavorable outcomes. The threshold to detect a patient with unfavorable outcome was an HCTS > 1. The three best individually performing biomarkers in outcome prediction were Aß40, Aß42, and neurofilament light. The optimal panel included IL-10, Aß40, and the HCTS reaching a partial area under the curve of the receiver operating characteristic of 3.4% (95% CI: 1.7-6.2) with a sensitivity of 90.9% (95% CI: 81.8-100) and specificity of 59.2% (95% CI: 40.8-69.4). Conclusion: Admission plasma levels of IL-10 and Aß40 significantly improve the prognostication ability of the HCTS after TBI.

Accuracy of C-reactive protein, procalcitonin, serum amyloid A and neopterin for low-dose CT-scan confirmed pneumonia in elderly patients: A prospective cohort study.

OBJECTIVE: The diagnosis of pneumonia based on semiology and chest X-rays is frequently inaccurate, particularly in elderly patients. Older (C-reactive protein (CRP); procalcitonin (PCT)) or newer (Serum amyloid A (SAA); neopterin (NP)) biomarkers may increase the accuracy of pneumonia diagnosis, but data are scarce and conflicting. We assessed the accuracy of CRP, PCT, SAA, NP and the ratios CRP/NP and SAA/NP in a prospective observational cohort of elderly patients with suspected pneumonia. METHODS: We included consecutive patients more than 65 years old, with at least one respiratory symptom and one symptom or laboratory finding suggestive of infection, and a working diagnosis of pneumonia. Low-dose CT scan and comprehensive microbiological testing were done in all patients. The index tests, CRP, PCT, SAA and NP, were obtained within 24 hours. The reference diagnosis was assessed a posteriori by a panel of experts considering all available data, including patients' outcome. We used area under the curve (AUROC) and Youden index to assess the accuracy and obtain optimal cut-off of the index tests. RESULTS: 200 patients (median age 84 years) were included; 133 (67%) had pneumonia. AUROCs for the diagnosis of pneumonia was 0.64 (95% CI: 0.56-0.72) for CRP; 0.59 (95% CI: 0.51-0.68) for PCT; 0.60 (95% CI: 0.52-0.69) for SAA; 0.41 (95% CI: 0.32-0.49) for NP; 0.63 (95% CI: 0.55-0.71) for CRP/NP; and 0.61 (95% CI: 0.53-0.70) for SAA/NP. No cut-off resulted in satisfactory sensitivity or specificity. CONCLUSIONS: Accuracy of traditional (CRP, PCT) and newly proposed biomarkers (SAA, NP) and ratios of CRP/NP and SAA/NP was too low to help diagnosing pneumonia in the elderly. CRP had the highest AUROC. CLINICAL TRIAL REGISTRATION: NCT02467092.

Interleukin 10 and Heart Fatty Acid-Binding Protein as Early Outcome Predictors in Patients With Traumatic Brain Injury.

Background: Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown predictive values for the presence of intracranial lesions. Aim: To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100ß, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors. Methods: Blood samples from patients with acute TBI (all severities) were collected <24 h post trauma. The outcome was measured >6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE≥5)/unfavorable outcome (GOSE ≤ 4) and complete (GOSE = 8)/incomplete (GOSE ≤ 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities. Results: When sensitivity was set at 95-100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities. Conclusion: Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100ß and clinical parameters improves outcome prediction models in TBI.

Biomarkers predictive value for early diagnosis of Stroke-Associated Pneumonia.

To confirm the diagnostic accuracy of candidate biomarkers in stroke-associated pneumonia (SAP), we prospectively enrolled ischemic stroke patients with NIHSS ≥ 10 on admission from March-2016 to August-2017. Blood samples were collected at baseline, 24 and 48 h after stroke onset. Biomarkers (MR-proADM, suPAR, SAA) were determined by immunoassays. Regarding biomarkers, MR-proADM at 24 h (P = 0.04) and both suPAR and SAA at 48 h (P = 0.036 and P = 0.057) were associated with pneumonia. The combination of SAA > 25.15 mg/dL and suPAR> 3.14 ng/mL at 48 h had 80% sensitivity and 95.8% specificity when both biomarkers were above the cut-off. The evaluated biomarkers represent promising tools to be evaluated in future large, prospective studies on SAP. An accurate SAP diagnosis by thorax CT might help to reduce variability in such studies.

Neopterin plasma concentrations in patients with aneurysmal subarachnoid hemorrhage: correlation with infection and long-term outcome.

OBJECT Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high rates of mortality and morbidity. The main predictor for the poor outcome is the World Federation of Neurosurgical Societies (WFNS) scale. However, this scale does not take into account proinflammatory events, such as infection occurring after the aSAH, which could modify the long-term status of patients. The aim of this study was to evaluate neopterin as an inflammatory biomarker for outcome and infection prediction in aSAH patients. METHODS Plasma concentrations of neopterin were measured in 61 aSAH patients (22 male and 39 female; mean age [± SD] 52.8 ± 11.8 years) using a commercial ELISA kit. Samples were collected daily for 10 days. Outcome at 12 months was determined using the Glasgow Outcome Scale (GOS) and dichotomized as poor (GOS score 1, 2, or 3) or good (GOS score 4 or 5). Infection was determined by the presence of a positive bacterial culture. RESULTS Patients with poor outcome at 12 months had higher concentrations of neopterin than patients with good outcome. In the same way, patients who had an infection during the hospitalization had significantly higher concentrations of neopterin than patients without infection (p = 0.001). Moreover, neopterin concentrations were significantly (p < 0.008) elevated in infected patients 2 days before infection detection and antibiotic therapy. CONCLUSIONS Neopterin is an efficient outcome predictor after aSAH. Furthermore, it is able to differentiate between infected and uninfected patients as early as 2 days before clinical signs of infection, facilitating earlier antibiotic therapy and better management.

Measuring Serum Amyloid A for Infection Prediction in Aneurysmal Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high rates of mortality and morbidity. Nosocomial infections, such as pneumonia or urinary tract infections, are among the main causes of worsening outcomes and death. The aim of this study was to discover a biomarker to predict infection in aSAH patients. For this purpose, the plasma of infected and noninfected patients was compared using quantitative mass spectrometry. The most interesting differentially expressed proteins were selected for validation by immunoassays on plasma samples taken from patients (n = 81) over 10 days of hospitalization. Predictive performances were established using Mann-Whitney U tests and receiver operating characteristic curves. Quantitative proteomics identified 17 significantly regulated proteins. Of these, levels of serum amyloid A (SAA) were significantly higher in infected patients (p < 0.007). ELISA confirmed that the concentrations were significantly higher (p < 0.002) already at hospital admission in patients who subsequently developed an infection during their hospitalization, (AUC of 76%) for a cutoff value of 90.9 µg/mL. Our data suggested that measuring SAA could be an efficient means of detecting patients susceptible of developing an infection during hospitalization after an aSAH. Its predictive capacity could lead to earlier antibiotherapy, improved patient management, and potentially better long-term outcomes.

Distribution and radiosensitizing effect of cholesterol-coupled Dbait molecule in rat model of glioblastoma.

BACKGROUND: Glioma is the most aggressive tumor of the brain and the most efficient treatments are based on radiotherapy. However, tumors are often resistant to radiotherapy due to an enhanced DNA repair activity. Short and stabilized DNA molecules (Dbait) have recently been proposed as an efficient strategy to inhibit DNA repair in tumor. METHODOLOGY/PRINCIPAL FINDINGS: The distribution of three formulations of Dbait, (i) Dbait alone, (ii) Dbait associated with polyethylenimine, and (iii) Dbait linked with cholesterol (coDbait), was evaluated one day after intratumoral delivery in an RG2 rat glioma model. Dbait molecule distribution was assessed in the whole organ with 2D-FRI and in brain sections. CoDbait was chosen for further studies given its good retention in the brain, cellular localization, and efficacy in inducing the activation of DNA repair effectors. The radiosensitizing effect of coDbait was studied in four groups of rats bearing RG2-glioma: no treatment, radiotherapy only, coDbait alone, and CoDbait with radiotherapy. Treatment started 7 days after tumor inoculation and consisted of two series of treatment in two weeks: coDbait injection followed by a selective 6-Gy irradiation of the head. We evaluated the radiosensitizing effect using animal survival, tumor volume, cell proliferation, and vasculature characteristics with multiparametric MRI. CoDbait with radiotherapy improved the survival of rats bearing RG2-glioma by reducing tumor growth and cell proliferation without altering tumor vasculature. CONCLUSION/SIGNIFICANCE: coDbait is therefore a promising molecular therapy to sensitize glioma to radiotherapy.