Diagnosis and management of diabetes insipidus for the internist: an update.

Diabetes insipidus is a disorder characterized by excretion of large amounts of hypotonic urine. Four entities have to be differentiated: central diabetes insipidus resulting from a deficiency of the hormone arginine vasopressin (AVP) in the pituitary gland or the hypothalamus, nephrogenic diabetes insipidus resulting from resistance to AVP in the kidneys, gestational diabetes insipidus resulting from an increase in placental vasopressinase and finally primary polydipsia, which involves excessive intake of large amounts of water despite normal AVP secretion and action. Distinguishing between the different types of diabetes insipidus can be challenging. A detailed medical history, physical examination and imaging studies are needed to detect the aetiology of diabetes insipidus. Differentiation between the various forms of hypotonic polyuria is then done by the classical water deprivation test or the more recently developed hypertonic saline or arginine stimulation together with copeptin (or AVP) measurement. In patients with idiopathic central DI, a close follow-up is needed since central DI can be the first sign of an underlying pathology. Treatment of diabetes insipidus or primary polydipsia depends on the underlying aetiology and differs in central diabetes insipidus, nephrogenic diabetes insipidus and primary polydipsia. This review will discuss issues and newest developments in diagnosis, differential diagnosis and treatment, with a focus on central diabetes insipidus.

Copeptin in the differential diagnosis of hypotonic polyuria.

COPEPTIN: Copeptin is secreted in equimolar amount to Arginine Vasopressin (AVP) but can easily be measured with a sandwich immunoassay. Both peptides, copeptin and AVP, show a high correlation. Accordingly, copeptin mirrors the amount of AVP in the circulation and its measurement provides an attractive marker in the differential diagnosis of diabetes insipidus. THE POLYURIA POLYDIPSIA SYNDROME: Diabetes insipidus-either central or nephrogenic-has to be differentiated from primary polydipsia. Differentiation is crucial since wrong treatment can have deleterious consequences. Since many decades, the "gold standard" for differential diagnosis has been the classical water deprivation test, which has several limitations leading to an overall limited diagnostic accuracy. In addition, the test has a long duration of 17 hours and is cumbersome for patients. Clinical signs and symptoms as well as MRI characteristics overlap between patients with diabetes insipidus and primary polydipsia. Direct measurement of AVP upon osmotic stimulation was first shown to overcome these limitations, but failed to enter clinical practice mainly due to technical limitations of the AVP assay. COPEPTIN AS DIAGNOSTIC TOOL IN THE POLYURIA POLYDIPSIA SYNDROME: We have recently shown that copeptin, without prior water deprivation, identifies patients with nephrogenic diabetes insipidus. On the other hand, for the more difficult differentiation between central diabetes insipidus and primary polydipsia, a copeptin level of 4.9 pmol/L stimulated with hypertonic saline infusion differentiates between these two entities with a high diagnostic accuracy, and is superior to the water deprivation test. It is important to note that close sodium monitoring during the hypertonic saline test is a prerequisite. CONCLUSION: Therefore, we propose that copeptin upon hypertonic saline infusion should become the new standard test in the differential diagnosis of diabetes insipidus.

Cytokines and Cortisol - predictors of treatment response to corticosteroids in community-acquired pneumonia?

BACKGROUND: A previous study found community-acquired pneumonia (CAP) patients with imbalance of high inflammation and discordantly low cortisol levels to benefit most from adjunctive corticosteroid treatment. Our aim was to validate this hypothesis in a preplanned secondary analysis of the randomized controlled STEP trial. METHODS: Patients included in the STEP trial receiving 50 mg prednisone or placebo for 5 days were categorized based on pro-inflammatory cytokines (Interleukin-6/8/MCP-1), CRP and cortisol levels on admission into four groups (high/low inflammation and high/low cortisol). The primary combined end-point was mortality or ICU admission within 30 days. RESULTS: In total, 632 patients (315 prednisone, 317 placebo) were included in this analysis. Prednisone did not significantly reduce the risk for the primary end-point in patients with high cytokines/low cortisol and in any other subgroups. However, we noted some differences in the strength of corticosteroid effect in the different subgroups with stronger effects in patients with high cytokines [OR 0.44 (0.10,1.72)] compared to patients with low cytokines [OR 0.68 (0.30,1.5)] (P-interaction = 0.600). The effects did not differ according to cortisol levels. CONCLUSION: The imbalance of high inflammation state and low cortisol levels did not predict treatment response to corticosteroids in patients with CAP. However, in line to previous research, inflammation as measured by cytokine levels irrespective of cortisol tended to predict treatment response to corticosteroids in CAP. Whether this concept may help to personalize corticosteroids to patients most likely benefitting from this treatment needs to be tested in future intervention trials.

Hyponatremia and activation of vasopressin secretion are both independently associated with 30-day mortality: results of a multicenter, observational study.

BACKGROUND: Hyponatremia is a common feature of acute illness and associated with increased mortality. This may be explained by a stress-mediated activation of the vasopressin system with an increase in free-water reabsorption. OBJECTIVES: To investigate whether the association between hyponatremia and mortality could be explained by activation of the vasopressin system. METHODS: We prospectively enrolled adult, medical patients seeking emergency care in three centres in Switzerland, France and the United States. We investigated associations between admission plasma sodium and copeptin, a stable portion of the vasopressin-precursor peptide, with 30-day mortality. We performed uni- and multivariate regression analysis. RESULTS: Of 6962 included patients, 18% had hyponatremia (sodium ≤135 mmol L-1 ), which doubled their risk for mortality compared to patients with normonatremia (8.3% vs. 3.8%). This association was confirmed in a multivariate-adjusted logistic regression analysis [adjusted odds ratio (OR) 1.47, 95% CI 1.12-1.93, P = 0.005]. Vasopressin levels, mirrored by copeptin, were also increased in nonsurvivors and strongly associated with mortality (adjusted OR 3.42, 95% CI 2.76-4.25, P < 0.001). The association between hyponatremia and mortality remained unchanged when adding copeptin levels to the regression model (fully adjusted OR 1.53, 95% CI 1.16-2.00, P = 0.002). CONCLUSION: This prospective study including medical patients upon emergency room admission found hyponatremia as well as an activation of the vasopressin system to be independently associated with mortality. This suggests that stress- and vasopressin-independent mechanisms are responsible for the association of low sodium levels with mortality.

Serum neurofilament light chain in patients with acute cerebrovascular events.

BACKGROUND AND PURPOSE: Serum neurofilaments are markers of axonal injury. We addressed their diagnostic and prognostic role in acute ischemic stroke (AIS) and transient ischemic attack (TIA). METHODS: Nested within a prospective cohort study, we compared levels of serum neurofilament light chain (sNfL) drawn within 24 h from symptom onset in patients with AIS or TIA. Patients without magnetic resonance imaging on admission were excluded. We assessed whether sNfL was associated with: (i) clinical severity on admission, (ii) diagnosis of AIS vs. TIA, (iii) infarct size on admission magnetic resonance diffusion-weighted imaging (MR-DWI) and (iv) functional outcome at 3 months. RESULTS: We analyzed 504 patients with AIS and 111 patients with TIA. On admission, higher National Institutes of Health Stroke Scale (NIHSS) scores were associated with higher sNfL: NIHSS score < 7, 13.1 pg/mL [interquartile range (IQR), 5.3-27.8]; NIHSS score 7-15, 16.7 pg/mL (IQR, 7.4-34.9); and NIHSS score > 15, 21.0 pg/mL (IQR, 9.3-40.4) (P = 0.01). Compared with AIS, patients with TIA had lower sNfL levels [9.0 pg/mL (95% confidence interval, 4.0-19.0) vs. 16.0 pg/mL (95% confidence interval, 7.3-34.4), P < 0.001], also after adjusting for age and NIHSS score (P = 0.006). Among patients with AIS, infarct size on admission MR-DWI was not associated with sNfL, either in univariate analysis (P = 0.15) or after adjusting for age and NIHSS score on admission (P = 0.56). Functional outcome 3 months after stroke was not associated with sNfL after adjusting for established predictors. CONCLUSIONS: In conclusion, among patients admitted within 24 h of AIS or TIA onset, admission sNfL levels were associated with clinical severity on admission and TIA diagnosis, but not with infarct size on MR-DWI acquired on admission or functional outcome at 3 months.

[Diagnostics and treatment of acromegaly : Necessity for targeted monitoring of comorbidities]. / Diagnostik und Therapie der Akromegalie : Notwendigkeit der gezielten Überwachung von Komorbiditäten.

Acromegaly is a rare and severe condition, presenting with typical signs and symptoms. The diagnosis is often initially made years after the first manifestations of the disease. In more than 99% of patients the disease is caused by a benign pituitary tumor that secretes growth hormone (GH). The diagnosis is based on the presence of increased insulin-like growth factor 1 (IGF-1) levels and a lack of GH suppression in the oral glucose tolerance test. The standard imaging procedure for tumor detection is magnetic resonance imaging in the region of the sella turcica. Treatment includes surgical, drug and radiation therapy. Important factors are an intensive aftercare of the patient, controls for detection of tumor recurrence and pituitary insufficiency as well as assessment of various organ functions and risk constellations. Patient care should involve close cooperation between endocrinologists, neurosurgeons and general practitioners as well as other specialist disciplines.

Predictors of nonresponse to fluid restriction in hyponatraemia due to the syndrome of inappropriate antidiuresis.

BACKGROUND: Fluid restriction (FR), the first-line treatment for hyponatraemia due to the syndrome of inappropriate antidiuresis (SIAD), often does not lead to successful correction of hyponatraemia. Therefore, predictive markers of treatment response are desirable. We evaluated routinely measured serum (s) and urine (u) parameters, s-copeptin and s-mid-regional pro-atrial natriuretic peptide (s-MR-proANP), as possible predictors of FR response. METHODS: In this prospective observational study, we included patients with profound hyponatraemia (s-sodium <125 mmol L-1 ) due to SIAD. Patients were classified as FR responders (increase in s-sodium concentration of >3 mmol L-1 within 24 h) or nonresponders (increase of ≤3 mmol L-1 within 24 h). Initial laboratory parameters were compared between groups with logistic regression analysis. RESULTS: Of 106 SIAD patients analysed, 82 underwent treatment with FR; 48 (59%) patients showed a successful response to FR and 34 (41%) were considered nonresponders. High levels of u-sodium and u-osmolality were significantly associated with nonresponse to FR [odds ratio (OR) 15.0, 95% confidence interval (CI) 2.4-95.8, P = 0.004 and OR 34.8, 95% CI 1.2-1038.8, P = 0.041, respectively). The association of u-sodium and nonresponse remained significant also after adjustment for diuretic use. Lower levels of s-MR-proANP were associated with nonresponse (OR 0.03, 95% CI 0.003-0.3, P = 0.004), whereas s-copeptin was not significantly associated with response to FR. CONCLUSION: Easily measured laboratory parameters, especially u-sodium, correlate with therapeutic response and identify patients most likely to fail to respond to FR. Measurement of these parameters may facilitate early treatment choice in patients with SIAD.

Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a 6-year prospective follow-up study.

OBJECTIVE: Prediction of long-term outcomes in patients with community-acquired pneumonia (CAP) is incompletely understood. We investigated the value of clinical risk scores [pneumonia severity index (PSI) and CURB-65] (Confusion, Urea, Respiratory rate, Blood Pressure, Age >65 years) and blood biomarkers of different physiopathological pathways in predicting long-term survival in a well-characterized cohort of patients with CAP enrolled in an antibiotic stewardship trial. DESIGN, SETTING AND SUBJECTS: Patients admitted with CAP to six medical centres in Switzerland were prospectively followed for 6 years. Cox regression models and area under the receiver operating characteristics curve (AUC) were used to investigate associations between initial risk assessment and all-cause mortality. MAIN OUTCOME MEASURE: All-cause mortality during a 6-year follow-up period. RESULTS: Six-year mortality in the present cohort (median age 73 years) was 45.1% [95% confidence interval (CI) 41.8-48.3%]. Initial PSI and CURB-65 scores both had excellent long-term prognostic accuracy, with a stepwise increase in mortality per risk class. The hazard ratios (95% CI) of the highest PSI and CURB-65 classes (reference: lowest class) were 38.0 (14.0-103.0) and 7.8 (2.2-14.5), respectively, after 6 years. The addition of inflammatory (pro-adrenomedullin) and cardiac (pro-atrial natriuretic peptide) blood biomarkers measured upon hospital admission further improved the prognostic capabilities of the PSI (AUC increase from 0.79 to 0.83; P < 0.0001) and the CURB-65 score (AUC increase from 0.73 to 0.80; P < 0.001). CONCLUSION: Risk assessment using clinical scores allowed accurate long-term prognostication, which was further improved by the addition of two inflammatory (pro-adrenomedullin) and cardiac (pro-atrial natriuretic peptide) blood biomarkers. These data provide a rationale for a more risk-adapted, 'personalized' strategy for long-term management of patients with CAP.

Mid-regional pro-atrial natriuretic peptide and the assessment of volaemic status and differential diagnosis of profound hyponatraemia.

BACKGROUND: Hyponatraemia is common and its differential diagnosis and consequent therapy management is challenging. The differential diagnosis is mainly based on the routine clinical assessment of volume status, which is often misleading. Mid-regional pro-atrial natriuretic peptide (MR-proANP) is associated with extracellular and cardiac fluid volume. METHODS: A total of 227 consecutive patients admitted to the emergency department with profound hypo-osmolar hyponatraemia (Na < 125 mmol L(-1) ) were included in this prospective multicentre observational study conducted in two tertiary centres in Switzerland. A standardized diagnostic evaluation of the underlying cause of hyponatraemia was performed, and an expert panel carefully evaluated volaemic status using clinical criteria. MR-proANP levels were compared between patients with hyponatraemia of different aetiologies and for assessment of volume status. RESULTS: MR-proANP levels were higher in patients with hypervolaemic hyponatraemia compared to patients with hypovolaemic or euvolaemic hyponatraemia (P = 0.0002). The area under the curve (AUC) to predict an excess of extracellular fluid volume, compared to euvolaemia, was 0.73 [95% confidence interval (CI) 0.62-0.84]. Additionally, in multivariate analysis, MR-proANP remained an independent predictor of excess extracellular fluid volume after adjustment for congestive heart failure (P = 0.012). MR-proANP predicted the syndrome of inappropriate antidiuresis (SIAD) versus hypovolaemic and hypervolaemic hyponatraemia with an AUC of 0.77 (95% CI 0.69-0.84). CONCLUSION: MR-proANP is associated with extracellular fluid volume in patients with hyponatraemia and remains an independent predictor of hypervolaemia after adjustment for congestive heart failure. MR-proANP may be a marker for discrimination between the SIAD and hypovolaemic or hypervolaemic hyponatraemia.

Inflammatory responses predict long-term mortality risk in community-acquired pneumonia.

Long-term outcomes in patients surviving community-acquired pneumonia (CAP) are still incompletely understood. This study investigates the association of clinical parameters and blood markers with long-term mortality. We prospectively followed 877 CAP patients from a previous multicentre trial for 18 months follow-up and investigated all-cause mortality following hospital discharge. Overall mortality was 17.3% (95% CI 14.8-19.8%) with a 12.8% (95% CI 10.9-15.0%) mortality incidence rate per year. Initial risk assignment using the Pneumonia Severity Index was accurate during the 18 month follow-up. Multivariable regression models (hazard ratio, 95% CI) designated the following as independent risk factors for long-term mortality: male sex (1.7, 1.2-2.5); chronic obstructive pulmonary disease (1.5, 1.1-2.1); neoplastic disease (2.5, 1.7-3.7); and highest quartile of peak pro-adrenomedullin level (3.3, 1.7-6.2). Initial presentation with temperature>38.7°C (0.4, 0.2-0.6), chills (0.6, 0.4-0.99) and highest quartile of the inflammatory marker C-reactive-protein (0.3, 0.2-0.5) were independent protective factors. A weighted risk score based on these variables showed good discrimination (area under receiver operating characteristic curve 0.78, 95% CI 0.74-0.82). Pronounced clinical and laboratory signs of systemic inflammatory host response upon initial hospital stay were associated with favourable long-term prognosis. Further studies should address whether closer monitoring of high-risk CAP patients after hospital discharge favourably impacts long-term mortality.

Prognostic value of procalcitonin in community-acquired pneumonia.

The prognostic value of procalcitonin (PCT) levels to predict mortality and other adverse events in community-acquired pneumonia (CAP) remains undefined. We assessed the performance of PCT overall, stratified into four predefined procalcitonin tiers (< 0.1, 0.1-0.25, > 0.25-0.5, >0.5 µg·L⁻¹) and stratified by Pneumonia Severity Index (PSI) and CURB-65 (confusion, urea >7 mmol·L⁻¹, respiratory frequency ≥ 30 breaths·min⁻¹, systolic blood pressure < 90 mmHg or diastolic blood pressure ≤ 60 mmHg, and age ≥ 65 yrs) risk classes to predict all-cause mortality and adverse events within 30 days follow-up in 925 CAP patients. In receiver operating characteristic curves, initial PCT levels performed only moderately for mortality prediction (area under the curve (AUC) 0.60) and did not improve clinical risk scores. Follow-up measurements on days 3, 5 and 7 showed better prognostic performance (AUCs 0.61, 0.68 and 0.73). For prediction of adverse events, the AUC was 0.66 and PCT significantly improved the PSI (from 0.67 to 0.71) and the CURB-65 (from 0.64 to 0.70). In Kaplan-Meier curves, PCT tiers significantly separated patients within PSI and CURB-65 risk classes for adverse events prediction, but not for mortality. Reclassification analysis confirmed the added value of PCT for adverse event prediction, but not mortality. Initial PCT levels provide only moderate prognostic information concerning mortality risk and did not improve clinical risk scores. However, PCT was helpful during follow-up and for prediction of adverse events and, thereby, improved the PSI and CURB65 scores.

Anterior pituitary axis hormones and outcome in acute ischaemic stroke.

BACKGROUND: Early and accurate prediction of outcome in acute stroke is important and influences risk-optimized therapeutic strategies. Endocrine alterations of the hypothalamic-pituitary axis are amongst the first measurable alterations after cerebral ischaemia. We therefore evaluated the prognostic value of cortisol, triiodothyronine (T3), free thyroxine (fT4), thyroid-stimulating hormone (TSH) and growth hormone (GH) in patients with an acute ischaemic stroke. METHODS: In an observational study including 281 patients with ischaemic stroke, anterior pituitary axis hormones (i.e. cortisol, T3, fT4, TSH and GH) were simultaneously assessed to determine their value to predict functional outcome and mortality within 90 days and 1 year. RESULTS: In receiver operating characteristic curve analysis, the prognostic accuracy of cortisol was higher compared to all measured hormones and was in the range of the National Institutes of Health Stroke Scale (NIHSS). Cortisol was an independent prognostic marker of functional outcome and death [odds ratio (OR) 1.0 (1.0-1.01) and 1.62 (1.37-1.92), respectively, P<0.0002 for both, adjusted for age and the NIHSS] in patients with ischaemic stroke, but added no significant additional predictive value to the clinical NIHSS score. CONCLUSION: Cortisol is an independent prognostic marker for death and functional outcome within 90 days and 1 year in patients with ischaemic stroke. By contrast, other anterior pituitary axis hormones such as peripheral thyroid hormones and GH are only of minor value to predict outcome in stroke.

The role of routine echocardiography in unselected patients with cerebrovascular ischaemic events.

BACKGROUND: Cardiac embolism is an important etiology of cerebrovascular ischaemic events (CIE). Echocardiography is routinely performed in patients with CIE despite guidelines recommending restriction of echocardiography to patients with clinically suspected cardioembolism. OBJECTIVE: The aim of this study was to examine the therapeutic impact and prognostic role of echocardiographic findings in an unselected population suffering from CIE. METHODS: Between November 2006 and November 2007, 319 patients with CIE underwent evaluation by transthoracic echocardiography (TTE) and in addition by transesophageal echocardiography (TEE) if deemed mandatory (n = 49). The combined clinical end-point included death or recurrent CIE, occurring during a follow-up period of 3 and 12 months, respectively. RESULTS: After 3 months of follow-up, the combined end-point was noted in 30 (9%) and after 12 months in 43 (13%) patients. In multivariate analysis, atrial fibrillation (AF) (HR 2.12, 95% CI 1.38-3.25; P < 0.001) and coronary artery disease (CAD: HR 1.85, 95% CI 1.21-2.81; P = 0.004) were predictors of events occurring during short-term follow-up. After 1 year of follow-up, AF (HR 1.67, 95% CI 1.19-2.32; P = 0.003) and CAD (HR 1.5, 95% CI 1.09-2.06; P = 0.01) were associated with the combined end-point. Echocardiographic parameters assessed at study entry were not independently related to an adverse outcome. CONCLUSION: Whereas AF and CAD appear to increase the risk of events after suffering from CIE, echocardiographic findings were not independently associated with the combined end-point of recurrent CIE or death.

Metformin induces glucose uptake in human preadipocyte-derived adipocytes from various fat depots.

To evaluate the effect of metformin on basal and insulin-induced glucose uptake in subcutaneous and visceral preadipocyte-derived adipocytes from obese and non-obese patients, preadipocytes were obtained from subcutaneous and visceral fat depots during abdominal surgery. Differentiation efficiency was evaluated by measurement of intracellular triglyceride accumulation. Preadipocyte-derived adipocytes were treated with metformin (1 mM) for 24 h with or without the addition of insulin (100 nM) for 20 min and glucose uptake was measured. In cells from each donor, intracellular triglyceride accumulation was more abundant in subcutaneous preadipocyte-derived adipocytes than in visceral preadipocyte-derived adipocytes (p < 0.001). Insulin stimulated glucose uptake in subcutaneous preadipocyte-derived adipocytes from both non-obese and obese patients (p < 0.001 vs. basal). In visceral preadipocyte-derived adipocytes, insulin did not increase basal glucose uptake. In subcutaneous preadipocyte-derived adipocytes from non-obese and obese patients, metformin alone increased glucose uptake to 2.7 +/- 0.2 (p < 0.001) and 2.1 +/- 0.1 fold (p < 0.001) respectively. Metformin increased glucose uptake in visceral preadipocyte-derived adipocytes from non-obese (1.7 +/- 0.1 fold vs. basal, p < 0.001) and obese (2.0 +/- 0.2 fold vs. basal, p < 0.001) patients. Combined treatment with metformin and insulin increased glucose uptake in subcutaneous preadipocyte-derived adipocytes from both non-obese and obese patients (p < 0.001 vs. insulin alone). In preadipocyte-derived adipocytes glucose uptake is induced by metformin independent of the fat depot origin of the preadipocytes (subcutaneous or visceral) and the obesity state of the patients (non-obese or obese). In adipocytes, metformin seems to induce glucose uptake independent of insulin suggesting an alternative mechanism of action of this drug.

Different strategies to overcome the effect of carbimazole on high- and low-dose radioiodine therapy: results from continuous dose-effect models.

BACKGROUND: Until now, it remains elusive which strategy - antithyroid drug withdrawal or increased radioiodine target doses - should be preferred to avoid the detrimental effect of antithyroid drugs in high- and low-dose radioiodine therapy, respectively. METHODS: We explored the effects of carbimazole on the 1-year post-radioiodine success and hypothyroidism rates by continuous dose-effect models, whereas success was defined as elimination of hyperthyroidism. Euthyroidism rates with and without carbimazole were calculated by numerical integration of the area between success and hypothyroidism curves. Target dose amplification factors for equal chance of success with and without carbimazole were calculated using logistic regression. RESULTS: Two hundred and twenty-eight patients were included in this study. Radioiodine target doses between 33 and 839 Gy were applied. Overall, the euthyroidism rates were 16.5% and 64.8%, while the hypothyroidism rates were 37.6% and 14.8% in Graves' disease and toxic nodular goitre, respectively. The success rate with simultaneous carbimazole (median dose 15 mg day(-1); range 2.5-60 mg day(-1)) was reduced over the entire target dose range in Graves' disease and toxic nodular goitre. The areas between curves for euthyroidism without and with simultaneous carbimazole were 127 and 43 Gy in Graves' disease and 178 and 128 Gy in toxic nodular goitre. The estimated radioiodine target dose amplification factor was 5.5 for Graves' disease and 3.0 for toxic nodular goitre. CONCLUSIONS: Simultaneous carbimazole reduces the euthyroidism rate, the aim of low-dose radioiodine therapy, over the entire target dose range in both Graves' disease and toxic nodular goitre. Therefore, antithyroid drug discontinuation should be preferred in low-dose radioiodine therapy. Conversely, escalation of the target dose should be preferred in high-dose radioiodine therapy.

Prognostic value of procalcitonin in Legionella pneumonia.

The diagnostic reliability and prognostic implications of procalcitonin (PCT) (ng/ml) on admission in patients with community-acquired pneumonia (CAP) due to Legionella pneumophila are unknown. We retrospectively analysed PCT values in 29 patients with microbiologically proven Legionella-CAP admitted to the University Hospital Basel, Switzerland, between 2002 and 2007 and compared them to other markers of infection, namely, C-reactive protein (CRP) (mg/l) and leukocyte count (10(9)/l), and two prognostic severity assessment scores (PSI and CURB65). Laboratory analysis demonstrated that PCT values on admission were >0.1 in over 93%, >0.25 in over 86%, and >0.5 in over 82% of patients with Legionella-CAP. Patients with adverse medical outcomes (59%, n = 17) including need for ICU admission (55%, n = 16) and/or inhospital mortality (14%, n = 4) had significantly higher median PCT values on admission (4.27 [IQR 2.46-9.48] vs 0.97 [IQR 0.29-2.44], p = 0.01), while the PSI (124 [IQR 81-147] vs 94 [IQR 75-116], p = 0.19), the CURB65 (2 [IQR 1-2] vs 1 [1-3], p = 0.47), CRP values (282 [IQR 218-343], p = 0.28 vs 201 [IQR 147-279], p = 0.28), and leukocyte counts (12 [IQR 10-21] vs 12 [IQR 9-15], p = 0.58) were similar. In receiver operating curves, PCT concentrations on admission had a higher prognostic accuracy to predict adverse outcomes (AUC 0.78 [95%CI 0.61-96]) as compared to the PSI (0.64 [95%CI 0.43-0.86], p = 0.23), the CURB65 (0.58 [95%CI 0.36-0.79], p = 0.21), CRP (0.61 [95%CI 0.39-0.84], p = 0.19), and leukocyte count (0.57 [95%CI 0.35-0.78], p = 0.12). Kaplan-Meier curves demonstrated that patients with initial PCT values above the optimal cut-off of 1.5 had a significantly higher risk of death and/or ICU admission (log rank p = 0.003) during the hospital stay. In patients with CAP due to Legionella, PCT levels on admission might be an interesting predictor for adverse medical outcomes.

Use of B-type natriuretic peptide in the risk stratification of community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is the leading infectious cause of death in developed countries. Risk stratification has previously been difficult. METHODS: Markers of cardiac stress (B-type natriuretic peptide, BNP) and inflammation (C-reactive protein, white blood cell count, procalcitonin) as well as the pneumonia severity index (PSI) were determined in 302 consecutive patients presenting to the emergency department (ED) with CAP. The accuracy of these parameters to predict death was evaluated as the primary endpoint. Prediction of treatment failure was considered as the secondary endpoint. RESULTS: B-type natriuretic peptide levels increased with rising disease severity as classified by the PSI (P = 0.015). BNP levels were significantly higher in nonsurvivors compared to survivors [median 439.2 (IQR 137.1-1384.6) vs. 114.3 (51.3-359.6) pg mL(-1), P < 0.001]. In a receiver operating characteristic analysis for the prediction of survival the area under the curve (AUC) for BNP was comparable to the AUC of the PSI (0.75 vs. 0.71, P = 0.52). Importantly, the combination of BNP and the PSI significantly improved the prognostic accuracy of the PSI alone (AUC 0.78 vs. 0.71; P = 0.02). The optimal cut-off for BNP was 279 pg mL(-1). The accuracy of BNP to predict treatment failure was identical to the accuracy to predict death (AUC 0.75). CONCLUSIONS: In patients with CAP, BNP levels are powerful and independent predictors of death and treatment failure. When used in conjunction with the PSI, BNP levels significantly improve the risk prediction when compared with the PSI alone.

Increase in high molecular weight adiponectin by bariatric surgery-induced weight loss.

AIM: To determine the changes in adiponectin multimers upon marked weight loss. METHODS: Plasma samples were obtained preoperatively and 3, 6, 12 and 24 months after surgery from 12 obese subjects undergoing weight loss-inducing bariatric surgery. Seven non-operated obese subjects served as controls. Plasma levels of adiponectin multimers were determined by protease digestion and Enzyme-Linked ImmunoSorbent Assay (ELISA) detection. In addition, adiponectin multimers were assessed by western blotting. RESULTS: In patients with weight loss after surgery but not in controls, total adiponectin and high molecular weight (HMW) adiponectin steadily increased during the observation period. Twenty-four months after surgery, the increase in total and HMW adiponectin was 2.2 +/- 0.46 and 1.4 +/- 0.3 microg/ml, respectively. In contrast, plasma concentrations of middle and low molecular weight adiponectin remained unchanged. CONCLUSIONS: The increase in plasma adiponectin levels observed 24 months after bariatric surgery depended on continuous weight loss and was completely attributable to the HMW complex.

A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH), also referred to as syndrome of inappropriate antidiuresis (SIAD), is the most common cause of hyponatremia characterized by extracellular hypotonicity and impaired urine dilution in the absence of any recognizable nonosmotic stimuli for the antidiuretic hormone arginine vasopressin (AVP). Hyponatremia in SIADH is primarily the result of excessive water retention caused by a combination of inappropriate antidiuresis and persistent fluid intake in the presence of impaired osmoregulated inhibition of thirst. It is sometimes aggravated by a sodium deficiency caused by a decreased intake or a secondary natriuresis in response to elevated extracellular volume. Inappropriate antidiuresis usually results from endogenous production of AVP that can be either ectopic (from a malignancy) or eutopic (from the hypothalamus/neurohypophysis). Regardless of its origin, different types of osmotic dysregulation of AVP have been reported with possibly fundamental deviations in treatment need and efficacy. A recent quantitative analysis of 50 patients with SIADH, which underwent serial measurements of copeptin during hypertonic saline infusion, revealed five distinct types of osmoregulatory defect ("type A to E") without affiliation to specific underlying diseases. In addition to apparently impaired osmoregulated inhibition of AVP release in the majority of patients, 12% of patients showed an AVP-independent mechanism of inappropriate antidiuresis, whilst 20% of them presented a reverse relation between hormone release and serum osmolality, presumably related to interrupted nonosmotic inhibitory pathways. The interference of these different types of SIAD with clinical presentation and therapy response will be a relevant subject for future research.