A simple clinical score to identify likely hepatitis B vaccination non-responders - data from a retrospective single center study.

BACKGROUND: About 10% of Hepatitis B vaccinated individuals mount no protective antibody levels against the hepatitis B surface antigen (HBs-Ag). Older age at primary immunization, obesity and smoking have previously been reported as risk factors associated with vaccine non-response. Here we tested whether these factors alone may allow selecting subjects that benefit from individualized immunization schedules. METHODS: Retrospective database analysis screening > 15,000 individual anti-HBs-IgG measurements. Non-responders (NR; anti-HBs-IgG < 10 IU/L) and low-responders (LR; anti-HBs-IgG 10-100 IU/L) were identified. Vaccine type, demographics, lifestyle, and immunological factors (leucocyte subset counts) were compared between NR, LR, and responders (R). RESULTS: We identified 113 LR/NR and compared them to 134 vaccine responders. We confirmed higher median age at primary vaccination (24.0 (R) vs. 30.5 (NR) vs. 31 (LR) years, p = 0.001), higher median BMI (23.2 kg/m2 (R) vs. 23.4 kg/m2 (NR) vs. 25.1 kg/m2 (LR), p = 0.001) and being a smoker (% smokers: 30.8% (R) vs. 57.1% (NR) vs. 52.5% (LR), p = 0.01) as factors negatively associated with anti-HBs-IgG levels. In a ROC analysis including these factors in a 6-point score, a high score predicted non-response with a specificity of 85% but at low sensitivity (47%). CONCLUSION: A simple clinical risk score based on age, obesity, and smoking identifies individuals with a high likelihood of vaccine failure. Non-responders with a low score are candidates for in-depth analyses to better understand the immunological causes of HBV vaccine non-response.

Procalcitonin-guided Antibiotic Treatment in Patients With Positive Blood Cultures: A Patient-level Meta-analysis of Randomized Trials.

BACKGROUND: Whether procalcitonin (PCT)-guided antibiotic management in patients with positive blood cultures is safe remains understudied. We performed a patient-level meta-analysis to investigate effects of PCT-guided antibiotic management in patients with bacteremia. METHODS: We extracted and analyzed individual data of 523 patients with positive blood cultures included in 13 trials, in which patients were randomly assigned to receive antibiotics based on PCT levels (PCT group) or a control group. The main efficacy endpoint was duration of antibiotic treatment. The main safety endpoint was mortality within 30 days. RESULTS: Mean duration of antibiotic therapy was significantly shorter for 253 patients who received PCT-guided treatment than for 270 control patients (-2.86 days [95% confidence interval [CI], -4.88 to -.84]; P = .006). Mortality was similar in both arms (16.6% vs 20.0%; P = .263). In subgroup analyses by type of pathogen, we noted a trend of shorter mean antibiotic durations in the PCT arm for patients infected with gram-positive organisms or Escherichia coli and significantly shorter treatment for subjects with pneumococcal bacteremia. In analysis by site of infection, antibiotic exposure was shortened in PCT subjects with Streptococcus pneumoniae respiratory infection and those with E. coli urogenital infections. CONCLUSIONS: This meta-analysis of patients with bacteremia receiving PCT-guided antibiotic management demonstrates lower antibiotic exposure without an apparent increase in mortality. Few differences were demonstrated in subgroup analysis stratified by type or site of infection but notable for decreased exposure in patients with pneumococcal pneumonia and E. coli urogenital infections.

Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: a patient-level meta-analysis of randomized trials.

BACKGROUND: The clinical utility of serum procalcitonin levels in guiding antibiotic treatment decisions in patients with sepsis remains unclear. This patient-level meta-analysis based on 11 randomized trials investigates the impact of procalcitonin-guided antibiotic therapy on mortality in intensive care unit (ICU) patients with infection, both overall and stratified according to sepsis definition, severity, and type of infection. METHODS: For this meta-analysis focusing on procalcitonin-guided antibiotic management in critically ill patients with sepsis of any type, in February 2018 we updated the database of a previous individual patient data meta-analysis which was limited to patients with respiratory infections only. We used individual patient data from 11 trials that randomly assigned patients to receive antibiotics based on procalcitonin levels (the "procalcitonin-guided" group) or the current standard of care (the "controls"). The primary endpoint was mortality within 30 days. Secondary endpoints were duration of antibiotic treatment and length of stay. RESULTS: Mortality in the 2252 procalcitonin-guided patients was significantly lower compared with the 2230 control group patients (21.1% vs 23.7%; adjusted odds ratio 0.89, 95% confidence interval (CI) 0.8 to 0.99; p = 0.03). These effects on mortality persisted in a subgroup of patients meeting the sepsis 3 definition and based on the severity of sepsis (assessed on the basis of the Sequential Organ Failure Assessment (SOFA) score, occurrence of septic shock or renal failure, and need for vasopressor or ventilatory support) and on the type of infection (respiratory, urinary tract, abdominal, skin, or central nervous system), with interaction for each analysis being > 0.05. Procalcitonin guidance also facilitated earlier discontinuation of antibiotics, with a reduction in treatment duration (9.3 vs 10.4 days; adjusted coefficient -1.19 days, 95% CI -1.73 to -0.66; p <  0.001). CONCLUSION: Procalcitonin-guided antibiotic treatment in ICU patients with infection and sepsis patients results in improved survival and lower antibiotic treatment duration.

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.

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.

[An Uncommon Cause of Arterial Hypertension]. / Seltene Ursache einer arteriellen Hypertonie.

An Uncommon Cause of Arterial Hypertension Abstract. A 54-year-old patient was suffering from arterial hypertension, which was not treated sufficiently despite an antihypertensive therapy with three different types of drugs. In addition, the patient complained an increase in weight of ten kilos during the last year and a new onset of diabetes mellitus type 2. Investigations as to secondary forms of hypertension by MRI revealed an adrenal tumor with a diameter of approx. 6 cm suspect for an adrenal carcinoma. An ACTH-independent cushing syndrome was diagnosed by 24-hour urines collection, 1-mg dexamethasone supression test, and midnight-cortisol measurement. After a laparoscopic tumor excision, histopathological analyses confirmed an adrenal carcinoma.

Validation of the hospital frailty risk score in a tertiary care hospital in Switzerland: results of a prospective, observational study.

OBJECTIVES: Recently, the Hospital Frailty Risk Score based on a derivation and validation study in the UK has been proposed as a low-cost, systematic screening tool to identify older, frail patients who are at a greater risk of adverse outcomes and for whom a frailty-attuned approach might be useful. We aimed to validate this Score in an independent cohort in Switzerland. DESIGN: Secondary analysis of a prospective, observational study (TRIAGE study). SETTING: One 600-bed tertiary care hospital in Aarau, Switzerland. PARTICIPANTS: Consecutive medical inpatients aged ≥75 years that presented to the emergency department or were electively admitted between October 2015 and April 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was all-cause 30-day mortality. Secondary endpoints were length of hospital stay, hospital readmission, functional impairment and quality of life measures. We used multivariate regression analyses. RESULTS: Of 4957 included patients, 3150 (63.5%) were classified as low risk, 1663 (33.5%) intermediate risk, and 144 (2.9%) high risk for frailty. Compared with the low-risk group, patients in the moderate risk and high-risk groups had increased risk for 30-day mortality (OR (OR) 2.53, 95% CI 2.09 to 3.06, p<0.001 and OR 4.40, 95% CI 2.94 to 6.57, p<0.001) with overall moderate discrimination (area under the ROC curve 0.66). The results remained robust after adjustment for important confounders. Similarly, we found longer length of hospital stay, more severe functional impairment and a lower quality of life in higher risk group patients. CONCLUSION: Our data confirm the prognostic value of the Hospital Frailty Risk Score to identify older, frail people at risk for mortality and adverse outcomes in an independent patient population. TRIAL REGISTRATION NUMBER: NCT01768494; Post-results.

The role of metabolomic markers for patients with infectious diseases: implications for risk stratification and therapeutic modulation.

INTRODUCTION: Metabolomics is a rapidly growing area of research. Metabolomic markers can provide information about the interaction of different organ systems, and thereby improve the understanding of physio-pathological processes, disease risk, prognosis and therapy responsiveness in a variety of diseases. Areas covered: In this narrative review of recent clinical studies investigating metabolomic markers in adult patients presenting with acute infectious disease, we mainly focused on patients with sepsis and lower respiratory tract infections. Currently, there is a growing body of literature showing that single metabolites from distinct metabolic pathways, as well as more complex metabolomic signatures are associated with disease severity and outcome in patients with systemic infections. These pathways include, among others, metabolomic markers of oxidative stress, steroid hormone and amino acid pathways, and nutritional markers. Expert commentary: Metabolic profiling has great potential to optimize patient management, to provide new targets for individual therapy and thereby improve survival of patients. At this stage, research mainly focused on the identification of new predictive signatures and less on metabolic determinants to predict treatment response. The transition from observational studies to implementation of novel markers into clinical practice is the next crucial step to prove the usefulness of metabolomic markers in patient care.

Influenza vaccine response profiles are affected by vaccine preparation and preexisting immunity, but not HIV infection.

Vaccines dramatically reduce infection-related morbidity and mortality. Determining factors that modulate the host response is key to rational vaccine design and demands unsupervised analysis. To longitudinally resolve influenza-specific humoral immune response dynamics we constructed vaccine response profiles of influenza A- and B-specific IgM and IgG levels from 42 healthy and 31 HIV infected influenza-vaccinated individuals. Pre-vaccination antibody levels and levels at 3 predefined time points after vaccination were included in each profile. We performed hierarchical clustering on these profiles to study the extent to which HIV infection associated immune dysfunction, adaptive immune factors (pre-existing influenza-specific antibodies, T cell responses), an innate immune factor (Mannose Binding Lectin, MBL), demographic characteristics (gender, age), or the vaccine preparation (split vs. virosomal) impacted the immune response to influenza vaccination. Hierarchical clustering associated vaccine preparation and pre-existing IgG levels with the profiles of healthy individuals. In contrast to previous in vitro and animal data, MBL levels had no impact on the adaptive vaccine response. Importantly, while HIV infected subjects with low CD4 T cell counts showed a reduced magnitude of their vaccine response, their response profiles were indistinguishable from those of healthy controls, suggesting quantitative but not qualitative deficits. Unsupervised profile-based analysis ranks factors impacting the vaccine-response by relative importance, with substantial implications for comparing, designing and improving vaccine preparations and strategies. Profile similarity between HIV infected and HIV negative individuals suggests merely quantitative differences in the vaccine response in these individuals, offering a rationale for boosting strategies in the HIV infected population.