Diagnostic and prognostic value of the D-dimer test in emergency department patients: secondary analysis of an observational study.

Background D-dimer measurement improves the rule-out of thromboembolic disease. However, little is known about the risk of false positive results for the diagnosis of thromboembolic disease and its prognostic value. Herein, we investigated factors influencing the accuracy of D-dimer and its prognostic value in a large cohort of emergency department (ED) patients. Methods This is a secondary analysis of a prospective observational single center, cohort study. Consecutive patients, for whom a D-dimer test was requested by the treating physician, were included. Associations of clinical parameters on admission with false positive D-dimer results for the diagnosis of thromboembolic disease were investigated with logistic regression analysis. Results A total of 3301 patients were included, of which 203 (6.1%) had confirmed thromboembolic disease. The negative and positive predictive values of the D-dimer test at the 0.5 mg/L cut-off were 99.9% and 11.4%, respectively. Several factors were associated with positive D-dimer results potentially falsely indicating thromboembolic disease in multivariate analysis including advanced age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.04-1.05, p < 0.001), congestive heart failure (CHF) (OR 2.79, 95% CI 1.77-4.4, p < 0.01), renal failure (OR 2.00, 95% CI 1.23-3.24, p = 0.005), history of malignancy (OR 2.6, 95% CI 1.57-4.31, p < 0.001), C-reactive protein (CRP) (OR 1.02, 95% CI 1.01-1.02, p < 0.001) and glomerular filtration rate (GFR) (OR 0.99, 95% CI 0.99-1.00, p = 0.003). Regarding its prognostic value, D-dimer was associated with a 30-day mortality (adjusted OR 1.05, 95% CI 1.02-1.09, p = 0.003) with an area under the curve (AUC) of 0.79. Conclusions While D-dimer allows an accurate rule-out of thromboembolic disease, its positive predictive value in routine ED patients is limited and largely influenced by age, comorbidities and acute disease factors. The strong prognostic value of D-dimer in this population warrants further investigation.

Asymmetric Dimethylarginine Predicts Long-Term Outcome in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

INTRODUCTION: In chronic obstructive pulmonary disease (COPD), there is an activation of the L-arginine nitric oxide pathway. Pulmonary obstruction causes to elevated nitric oxide (NO) levels, which lead to higher production of the NO-inhibiting metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). METHODS: We investigated the association of L-arginine, ADMA, and SDMA with clinical outcomes in a well-defined observational cohort of 150 patients with acute exacerbation of COPD. We measured L-arginine, ADMA, and SDMA by mass spectrometry in patients with pneumonic or non-pneumonic exacerbation of COPD included in a Swiss multicenter trial. We used Cox regression models to investigate the associations between blood marker levels and disease severity as well as all-cause mortality over a follow-up of 6.1 years. RESULTS: Six-year all-cause mortality was 54%. Admission levels of ADMA and SDMA (µmol L-1) were increased in 6-year non-survivors compared to survivors' median (0.60 vs. 0.46, p = 0.004; and 1.05 vs. 0.85, p = 0.012). In a multivariate Cox regression analysis, ADMA was associated with long-term mortality resulting in an age- and comorbidity-adjusted hazard ratio (HR) of 4.55 (95% confidence interval 1.02-20.43, p = 0.048). SDMA was only associated in univariate models and no association of L-arginine with outcome was found. CONCLUSION: ADMA was found to be an independent risk factor for long-term all-cause mortality in patients with acute exacerbation of COPD. Whether therapeutic modification of the L-arginine-nitric oxide pathway has the potential to improve outcome should be evaluated in future interventional trials.

Activation of the Serotonin Pathway is Associated with Poor Outcome in COPD Exacerbation: Results of a Long-Term Cohort Study.

BACKGROUND/INTRODUCTION: Indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine. An increase of its activity is associated with severity in patients with pneumonia. In chronic obstructive pulmonary disease (COPD) patients, an elevation of serotonin has been reported. Experimental models showed that cigarette smoke inhibits monoamine oxidase (MAO) leading to higher levels of serotonin. We investigated the prognostic ability of tryptophan, serotonin, kynurenine, IDO, and tryptophan hydroxylase (TPH) to predict short- and long-term outcomes in patients with a COPD exacerbation. METHODS: We measured tryptophan, serotonin, and kynurenine on admission plasma samples in patients with a COPD exacerbation from a previous trial by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). IDO and TPH were calculated as ratios of kynurenine over tryptophan, and serotonin over tryptophan, respectively. We studied their association with parameters measured in clinical routine at emergency department admission representing inflammation (C-reactive protein [CRP]), infection (procalcitonin [PCT]), oxygenation (SpO2), as well as patients' clinical outcome, confirmed by structured phone interviews. RESULTS: Mortality in the 149 included patients was 53.7% within six years of follow-up. While IDO activity showed strong positive correlations, tryptophan was negatively correlated with CRP and PCT. For 30-day adverse outcome defined as death and/or intensive care unit (ICU) admission, a multivariate regression analysis adjusted for age and comorbidities found strong associations for IDO activity (adjusted odds ratios of 31.4 (95%CI 1.1-857), p = 0.041) and TPH (adjusted odds ratios 27.0 (95%CI 2.2-327), p = 0.010). TPH also showed a significant association with mortality at 18 months, (hazard ratio 2.61 (95%CI 1.2-5.8), p = 0.020). CONCLUSION: In hospitalized patients with a COPD exacerbation, higher IDO and TPH activities independently predicted adverse short-term outcomes and TPH levels were also predictive of 18-month mortality. Whether therapeutic modulation of the serotonin pathway has positive effects on outcome needs further investigation.

Admission levels of asymmetric and symmetric dimethylarginine predict long-term outcome in patients with community-acquired pneumonia.

BACKGROUND: During infection, there is an activation of the L-arginine-nitric-oxide pathway, with a shift from nitric oxide synthesis to a degradation of L-arginine to its metabolites, asymmetric and symmetric dimethylarginine (ADMA and SDMA). However, the prognostic implications for short-term or long-term survival remains unclear. We investigated the association of L-arginine, ADMA, and SDMA with adverse clinical outcomes in a well-defined cohort of patients with community-acquired pneumonia (CAP). METHODS: We measured L-arginine, ADMA, and SDMA in 268 CAP patients from a Swiss multicenter trial by mass spectrometry and used Cox regression models to investigate associations between blood marker levels and disease severity as well as mortality over a period of 6 years. RESULTS: Six-year mortality was 44.8%. Admission levels of ADMA and SDMA (µmol/L) were correlated with CAP severity as assessed by the pneumonia severity index (r = 0.32, p < 0.001 and r = 0.56, p < 0.001 for ADMA and SDMA, respectively) and higher in 6-year non-survivors versus survivors (median 0.62 vs. 0.48; p < 0.001 and 1.01 vs. 0.85; p < 0.001 for ADMA and SDMA, respectively). Both ADMA and SDMA were significantly associated with long-term mortality (hazard ratios [HR] 4.44 [95% confidence intervals (CI) 1.84 to 10.74] and 2.81 [95% CI 1.45 to 5.48], respectively). The effects were no longer significant after multivariate adjustment for age and comorbidities. No association of L-arginine with severity and outcome was found. CONCLUSIONS: Both ADMA and SDMA show a severity-dependent increase in patients with CAP and are strongly associated with mortality. This association is mainly explained by age and comorbidities. TRIAL REGISTRATION: ISRCTN95122877 . Registered 31 July 2006.

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study.

BACKGROUND: As part of the immune defense during infection, an increase in enzyme activity of indoleamine 2,3-dioxygenase (IDO) leads to a breakdown of tryptophan to kynurenine. In previous animal studies, therapeutic antagonism of IDO resulted in reduced sepsis mortality. We investigated the prognostic ability of tryptophan, serotonin, kynurenine and IDO (represented by the ratio of kynurenine/tryptophan) to predict adverse clinical outcomes in patients with community-acquired pneumonia (CAP). METHODS: We measured tryptophan, serotonin and kynurenine on admission plasma samples from CAP patients included in a previous multicenter trial by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We studied their association with inflammation (C-reactive protein), infection (procalcitonin) and clinical outcome. RESULTS: Mortality in the 268 included patients was 45% within 6 years of follow-up. IDO and kynurenine showed a strong positive correlation with markers of infection (procalcitonin) and inflammation (C-reactive protein) as well as sepsis and CAP severity scores. Tryptophan showed similar, but negative correlations. In a multivariate regression analysis adjusted for age and comorbidities, higher IDO activity and lower tryptophan levels were strongly associated with short-term adverse outcome defined as death and/or ICU admission within 30 days with adjusted odds ratios of 9.1 [95% confidence interval (CI) 1.4-59.5, p=0.021] and 0.11 (95% CI 0.02-0.70, p=0.021). Multivariate analysis did not reveal significant associations for kynurenine and serotonin. CONCLUSIONS: In hospitalized CAP patients, higher IDO activity and lower tryptophan levels independently predicted disease severity and short-term adverse outcome. Whether therapeutic modulation of IDO has positive effects on outcome needs further investigation.

Long-term Prognosis in COPD Exacerbation: Role of Biomarkers, Clinical Variables and Exacerbation Type.

Long-term outcome prediction in COPD is challenging. We conducted a prospective 5-7-year follow-up study in patients with COPD to determine the association of exacerbation type, discharge levels of inflammatory biomarkers including procalctionin (PCT), C-reactive protein (CRP), white blood cell count (WBC) and plasma proadrenomedullin (ProADM), alone or combined with demographic/clinical characteristics, with long-term all-cause mortality in the COPD setting. The analyzed cohort comprised 469 patients with index hospitalization for pneumonic (n = 252) or non-pneumonic (n = 217) COPD exacerbation. Five-to-seven-year vital status was ascertained via structured phone interviews with patients or their household members/primary care physicians. We investigated predictive accuracy using univariate and multivariate Cox regression models and area under the receiver operating characteristic curve (AUC). After a median [25th-75th percentile] 6.1 [5.6-6.5] years, mortality was 55% (95%CI 50%-59%). Discharge ProADM concentration was strongly associated with 5-7-year non-survival: adjusted hazard ratio (HR)/10-fold increase (95%CI) 10.4 (6.2-17.7). Weaker associations were found for PCT and no significant associations were found for CRP or WBC. Combining ProADM with demographic/clinical variables including age, smoking status, BMI, New York Heart Association dyspnea class, exacerbation type, and comorbidities significantly improved long-term predictive accuracy over that of the demographic/clinical model alone: AUC (95%CI) 0.745 (0.701-0.789) versus 0.727 (0.681-0.772), (p) = .043. In patients hospitalized for COPD exacerbation, discharge ProADM levels appeared to accurately predict 5-7-year all-cause mortality and to improve long-term prognostic accuracy of multidimensional demographic/clinical mortality risk assessment.

Excluding infection through procalcitonin testing improves outcomes of congestive heart failure patients presenting with acute respiratory symptoms: results from the randomized ProHOSP trial.

BACKGROUND/OBJECTIVES: We sought to determine whether exclusion of infection and antibiotic stewardship with the infection biomarker procalcitonin improves outcomes in congestive heart failure (CHF) patients presenting to emergency departments with respiratory symptoms and suspicion of respiratory infection. METHODS: We performed a secondary analysis of patients with a past medical history of CHF formerly included in a Swiss multicenter randomized-controlled trial. The trial compared antibiotic stewardship according to a procalcitonin algorithm or state-of-the-art guidelines (controls). The primary endpoint was a 30-day adverse outcome (death, intensive care unit admission); the secondary endpoints included a 30-day antibiotic exposure. RESULTS: In the 110/233 analyzed patients (47.2%) with low initial procalcitonin (<0.25 µg/L), suggesting the absence of systemic bacterial infection, those randomized to procalcitonin guidance (n=50) had a significantly lower adverse outcome rate compared to controls (n=60): 4% vs. 20% (absolute difference -16.0%, 95% confidence interval (CI) -28.4% to -3.6%, P=0.01), and significantly reduced antibiotic exposure [days] (mean 3.7 ± 4.0 vs. 6.5 ± 4.4, difference -2.8 [95% CI, -4.4 to -1.2], P<0.01). When initial procalcitonin was ≥0.25 µg/L, procalcitonin-guided patients had significantly reduced antibiotic exposure due to early stop of therapy without any difference in adverse outcomes (25.8% vs. 24.6%, difference [95% CI] 1.2% [-14.5% to 16.9%, P=0.88]). CONCLUSIONS: CHF patients presenting to the emergency department with respiratory symptoms and suspicion for respiratory infection had decreased antibiotic exposure and improved outcomes when procalcitonin measurement was used to exclude bacterial infection and guide antibiotic treatment. These data provide further evidence for the potential harmful effects of antibiotic / fluid treatment when used instead of diuretics and heart failure medication in clinically symptomatic CHF patients without underlying infection.