stress hormones; risk assessment; adrenal insufficiency; respiratory tract infections; community-acquired pneumonia; prognosis; Corticosteroids
Popovic Milica, Blum Claudine A, Nigro Nicole, Mueller Beat, Schuetz Philipp, Christ-Crain Mirjam (2016), Benefit of adjunct corticosteroids for community-acquired pneumonia in diabetic patients., in Diabetologia
Wirz Sebastian A, Blum Claudine A, Schuetz Philipp, Albrich Werner C, Noppen Christoph, Mueller Beat, Christ-Crain Mirjam, Tarr Philip E, Tarr Philip E (2016), Pathogen- and antibiotic-specific effects of prednisone in community-acquired pneumonia., in The European respiratory journal
Blum Claudine Angela, Nigro Nicole, Briel Matthias, Schuetz Philipp, Ullmer Elke, Suter-Widmer Isabelle, Winzeler Bettina, Bingisser Roland, Elsaesser Hanno, Drozdov Daniel, Arici Birsen, Urwyler Sandrine Andrea, Refardt Julie, Tarr Philip, Wirz Sebastian, Thomann Robert, Baumgartner Christine, Duplain Herve, Burki Dieter, Zimmerli Werner, Rodondi Nicolas, Mueller Beat, Christ-Crain Mirjam (2015), Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial, in LANCET
, 385(9977), 1511-1518.
Blum Claudine Angela, Nigro Nicole, Briel Matthias, Schuetz Philipp, Ullmer Elke, Suter-Widmer Isabelle, Winzeler Bettina, Bingisser Roland, Elsaesser Hanno, Drozdov Daniel, Arici Birsen, Urwyler Sandrine Andrea, Refardt Julie, Tarr Philip, Wirz Sebastian, Thomann Robert, Baumgartner Christine, Duplain Hervé, Burki Dieter, Zimmerli Werner, Rodondi Nicolas, Mueller Beat, Christ-Crain Mirjam (2015), Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial., in Lancet (London, England)
, 385(9977), 1511-8.
Alan M., Grolimund E., Kutz A., Christ-Crain M., Thomann R., Falconnier C., Hoess C., Henzen C., Zimmerli W., Mueller B., Schuetz P. (2015), 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, in JOURNAL OF INTERNAL MEDICINE
, 278(2), 174-184.
Urwyler Sandrine A., Schuetz Philipp, Sailer Clara, Christ-Crain Mirjam (2015), Copeptin as a stress marker prior and after a written examination - the CoEXAM study, in STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS
, 18(1), 134-137.
Timper Katharina, Fenske Wiebke, Kuhn Felix, Frech Nica, Arici Birsen, Rutishauser Jonas, Kopp Peter, Allolio Bruno, Stettler Christoph, Mueller Beat, Katan Mira, Christ-Crain Mirjam (2015), Diagnostic Accuracy of Copeptin in the Differential Diagnosis of the Polyuria-polydipsia Syndrome: A Prospective Multicenter Study, in JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
, 100(6), 2268-2274.
Schuetz Philipp, Balk Robert, Briel Matthias, Kutz Alexander, Christ-Crain Mirjam, Stolz Daiana, Bouadma Lila, Wolff Michel, Kristoffersen Kristina B., Wei Long, Burkhardt Olaf, Welte Tobias, Schroeder Stefan, Nobre Vandack, Tamm Michael, Bhatnagar Neera, Bucher Heiner C., Luyt Charles-Edouard, Chastre Jean, Tubach Florence, Mueller Beat, Lacey Michael J., Ohsfeldt Robert L., Scheibling Cara M., Schneider John E. (2015), Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective, in CLINICAL CHEMISTRY AND LABORATORY MEDICINE
, 53(4), 583-592.
Grolimund Eva, Kutz Alexander, Marlowe Robert J., Voegeli Alaadin, Alan Murat, Christ-Crain Mirjam, Thomann Robert, Falconnier Claudine, Hoess Claus, Henzen Christoph, Zimmerli Werner, Mueller Beat, Schuetz Philipp (2015), Long-term Prognosis in COPD Exacerbation: Role of Biomarkers, Clinical Variables and Exacerbation Type, in COPD-JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
, 12(3), 295-305.
Nigro N., Winzeler B., Suter-Widmer I., Schuetz P., Arici B., Bally M., Blum C. A., Nickel C. H., Bingisser R., Bock A., Savoca K. Rentsch, Huber A., Mueller B., Christ-Crain M. (2015), Mid-regional pro-atrial natriuretic peptide and the assessment of volaemic status and differential diagnosis of profound hyponatraemia, in JOURNAL OF INTERNAL MEDICINE
, 278(1), 29-37.
De Marchis G. M. D. M. Gian Marco, Schneider J., Weck A. W. Anja, Fluri F. F. Felix, Foerch C. F. Christian, Schuetz P. S. Philipp, Buhl D. B. Daniela, Seiler M. S. Marleen, Morgenthaler N. M. Nils, Mattle H. P. M. Heinrich P., Mueller B. M. Beat, Christ-Crain M. C. C. Mirjam, Arnold M. A. Marcel, Katan M. K. Mira (2015), Mid-regional pro-atrial natriuretic peptide as independent outcome and aetiological ischemic stroke biomarker: Results from the CORISK Study, in INTERNATIONAL JOURNAL OF STROKE
, 10, 51-52.
Winzeler Bettina, Zweifel Christian, Nigro Nicole, Arici Birsen, Bally Martina, Schuetz Philipp, Blum Claudine Angela, Kelly Christopher, Berkmann Sven, Huber Andreas, Gentili Fred, Zadeh Gelareh, Landolt Hans, Mariani Luigi, Muller Beat, Christ-Crain Mirjam (2015), Postoperative Copeptin Concentration Predicts Diabetes Insipidus After Pituitary Surgery, in JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
, 100(6), 2275-2282.
Kutz Alexander, Briel Matthias, Christ-Crain Mirjam, Stolz Daiana, Bouadma Lila, Wolff Michel, Kristoffersen Kristina B., Wei Long, Burkhardt Olaf, Welte Tobias, Schroeder Stefan, Nobre Vandack, Tamm Michael, Bhatnagar Neera, Bucher Heiner C., Luyt Charles-Edouard, Chastre Jean, Tubach Florence, Mueller Beat, Schuetz Philipp (2015), Prognostic value of procalcitonin in respiratory tract infections across clinical settings, in CRITICAL CARE
, 19, 74.
Nigro Nicole, Winzeler Bettina, Suter-Widmer Isabelle, Schuetz Philipp, Arici Birsen, Bally Martina, Blum Claudine, Bingisser Roland, Bock Andreas, Huber Andreas, Mueller Beat, Nickel Christian H., Christ-Crain Mirjam (2015), Symptoms and Characteristics of Individuals with Profound Hyponatremia: A Prospective Multicenter Observational Study, in JOURNAL OF THE AMERICAN GERIATRICS SOCIETY
, 63(3), 470-475.
Zhydkov Andriy, Christ-Crain Mirjam, Thomann Robert, Hoess Claus, Henzen Christoph, Zimmerli Werner, Mueller Beat, Schuetz Philipp (2015), Utility of procalcitonin, C-reactive protein and white blood cells alone and in combination for the prediction of clinical outcomes in community-acquired pneumonia, in CLINICAL CHEMISTRY AND LABORATORY MEDICINE
, 53(4), 559-566.
Nigro Nicole, Christ-Crain Mirjam, Meier Christian (2014), [In Process Citation]., in Therapeutische Umschau. Revue thérapeutique
, 71(4), 229-37.
Fenske Wiebke Kristin, Christ-Crain Mirjam, Hörning Anna, Simet Jessica, Szinnai Gabor, Fassnacht Martin, Rutishauser Jonas, Bichet Daniel G, Störk Stefan, Allolio Bruno (2014), A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis., in Journal of the American Society of Nephrology : JASN
, 25(10), 2376-83.
Boeck Lucas, Gencay Mikael, Roth Michael, Hirsch Hans H, Christ-Crain Mirjam, Mueller Beat, Tamm Michael, Stolz Daiana (2014), Adenovirus-specific IgG maturation as a surrogate marker in acute exacerbations of COPD., in Chest
, 146(2), 339-47.
Mueller Cornelia, Blum Claudine A, Trummler Michael, Stolz Daiana, Bingisser Roland, Mueller Christian, Tamm Michael, Mueller Beat, Schuetz Philipp, Christ-Crain Mirjam (2014), Association of adrenal function and disease severity in community-acquired pneumonia., in PloS one
, 9(6), 99518-99518.
Nigro Nicole, Wildi Karin, Mueller Christian, Schuetz Philipp, Mueller Beat, Fluri Felix, Christ-Crain Mirjam, Katan Mira (2014), BNP but Not s-cTnln is associated with cardioembolic aetiology and predicts short and long term prognosis after cerebrovascular events., in PloS one
, 9(7), 102704-102704.
Siegenthaler Judith, Walti Carla, Urwyler Sandrine Andrea, Schuetz Philipp, Christ-Crain Mirjam (2014), Copeptin Concentrations During Psychological Stress: the PsyCo Study., in European journal of endocrinology / European Federation of Endocrine Societies
De Marchis Gian Marco, Weck Anja, Audebert Heinrich, Benik Steffen, Foerch Christian, Buhl Daniela, Schuetz Philipp, Jung Simon, Seiler Marleen, Morgenthaler Nils G, Mattle Heinrich P, Mueller Beat, Christ-Crain Mirjam, Arnold Marcel, Katan Mira (2014), Copeptin for the prediction of recurrent cerebrovascular events after transient ischemic attack: results from the CoRisk study., in Stroke; a journal of cerebral circulation
, 45(10), 2918-23.
Walti Carla, Siegenthaler Judith, Christ-Crain Mirjam (2014), Copeptin levels are independent of ingested nutrient type after standardised meal administration - the CoMEAL study., in Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals
, 19(7), 557-62.
Blum Claudine A, Mirza Uzma, Christ-Crain Mirjam, Mueller Beat, Schindler Christian, Puder Jardena J (2014), Copeptin levels remain unchanged during the menstrual cycle., in PloS one
, 9(5), 98240-98240.
Blum Claudine A, Nigro Nicole, Winzeler Bettina, Suter-Widmer Isabelle, Schuetz Philipp, Briel Matthias, Bingisser Roland, Zimmerli Werner, Ullmer Elke, Elsaesser Hanno, Tarr Philip, Wirz Sebastian, Thomann Robert, Hofmann Eveline, Rodondi Nicolas, Duplain Hervé, Burki Dieter, Mueller Beat, Christ-Crain Mirjam (2014), Corticosteroid treatment for community-acquired pneumonia--the STEP trial: study protocol for a randomized controlled trial., in Trials
, 15, 257-257.
Schuetz Philipp, Kutz Alexander, Grolimund Eva, Haubitz Sebastian, Demann Désirée, Vögeli Alaadin, Hitz Fabienne, Christ-Crain Mirjam, Thomann Robert, Falconnier Claudine, Hoess Claus, Henzen Christoph, Marlowe Robert J, Zimmerli Werner, Mueller Beat, ProHOSP Study Group (2014), Excluding infection through procalcitonin testing improves outcomes of congestive heart failure patients presenting with acute respiratory symptoms: results from the randomized ProHOSP trial., in International journal of cardiology
, 175(3), 464-72.
Frontzek Karl, Fluri Felix, Siemerkus Jakob, Müller Beat, Gass Achim, Christ-Crain Mirjam, Katan Mira (2014), Isolated insular strokes and plasma MR-proANP levels are associated with newly diagnosed atrial fibrillation: a pilot study., in PloS one
, 9(3), 92421-92421.
Grolimund Eva, Kutz Alexander, Marlowe Robert J, Vögeli Alaadin, Alan Murat, Christ-Crain Mirjam, Thomann Robert, Falconnier Claudine, Hoess Claus, Henzen Christoph, Zimmerli Werner, Mueller Beat, Schuetz Philipp, for the ProHOSP Study Group (2014), Long-term Prognosis in COPD Exacerbation: Role of Biomarkers, Clinical Variables and Exacerbation Type., in COPD
Kutz Alexander, Grolimund Eva, Christ-Crain Mirjam, Thomann Robert, Falconnier Claudine, Hoess Claus, Henzen Christoph, Zimmerli Werner, Mueller Beat, Schuetz Philipp (2014), Pre-analytic factors and initial biomarker levels in community-acquired pneumonia patients, in BMC ANESTHESIOLOGY
, 14, 102.
Zhydkov Andriy, Christ-Crain Mirjam, Thomann Robert, Hoess Claus, Henzen Christoph, Zimmerli Werner, Mueller Beat, Schuetz Philipp (2014), Utility of procalcitonin, C-reactive protein and white blood cells alone and in combination for the prediction of clinical outcomes in community-acquired pneumonia., in Clinical chemistry and laboratory medicine : CCLM / FESCC
Background: Community-acquired pneumonia (CAP) is associated with significant stress with activation of the hypothalamic-pituitary-adrenal (HPA) axis, morbidity and mortality and is the most common cause of death from infectious diseases in developed countries. Mortality rates for CAP have not changed significantly over several decades although new broad-spectrum antibiotics are available, suggesting that other factors are responsible for poor outcome. An abnormal increase in the inflammatory response is associated with poor outcome, and this occurs despite adequate antibiotic therapy. Thus, adjunctive therapies to antibiotics for the treatment of CAP are required. Corticosteroids have an effective intracellular anti-inflammatory activity which is indispensable for survival after exposure to infections. As early as 1955, favorable effects of corticosteroids were reported in patients with pneumococcal pneumonia. A small-sized multicenter randomized trial showed a significant reduction in hospital mortality in severe CAP with a seven-day continuous infusion of hydrocortisone (240mg/d), although this study was not powered for mortality. Another large, but retrospective single center study evaluated more than 300 patients and demonstrated in multivariate analysis that use of corticosteroids was associated with a lower mortality (7). More recently, two randomized controlled trials involving 200-300 patients showed controversial results. Two systematic reviews concluded that the available evidence suggests that administration of corticosteroids in patients with CAP might be beneficial, however, a large and adequately powered randomized trial is warranted to support this benefit before a recommendation can be made with regard to the use of corticosteroids in the treatment of CAP. Study Objectives: The current large and adequately powered randomized double-blind trial will determine the risks and benefits of adding corticosteroids to the treatment of patients with CAP. We will compare a treatment with 7 days of corticosteroids with placebo in patients with CAP with respect to the primary endpoint of time to clinical stability. We hypothesize that use of corticosteroids will lead to a 25% relative risk reduction for death and clinical instability.Study Design & Setting: This is an investigator-initiated, double-blind randomized multicentre trial. All patients hospitalized with CAP will be included and randomized 1:1 either to corticosteroid or to placebo. Due to power calculations, a sample size of 800 (400 per group) will be needed to achieve a statistical power of 85%. We consider loss to follow up for the primary endpoint of clinical stability in this sample of hospitalized patients as unlikely. We intend to recruit the 800 study participants from December 2009 to June 2014. Centers: University Hospital Basel, cantonal hospitals of Bruderholz, Liestal, Aarau, Solothurn and Delémont, University Hospital Bern (Inselspital Bern). Study participants:Inclusion criteria: Patients 18 years of age or older admitted for hospitalization from the community or a nursing home with CAP. CAP is defined by a new infiltrate on chest radiograph and the presence of one or several of the following acute respiratory signs or symptoms, cough, sputum production, dyspnea, core body temperature >38.0° C, auscultatory findings of abnormal breath sounds and rales and leukocyte count >10 or <4 x 109 cells L-1. Exclusion criteria: Patients permanently unable to give written informed consent, e.g. with severe dementia, other permanent cognitive impairment or legal guardian; Patients with active intravenous drug use; severe immunosuppression; patients with cystic fibrosis as well as patients with active tuberculosis; patients with acute burn injury; patients with acute gastrointestinal bleeding within 3 months of the current hospitalization; patients with a condition requiring more than 0.5mg/kg/d prednisone equivalent; pregnancy or breast feeding; patients with known adrenal insufficiency. Intervention: All patients with community-acquired pneumonia willing to participate in the study are randomized to either corticosteroid treatment or placebo treatment for 7 days. Clinical stability is monitored 12 hourly and blood sampling is performed at days 3, 5 and 7. At day 30 and 180 all patients have a telephone follow-up interview. Study endpoints: Primary Endpoint: The primary endpoint is time to clinical stability. Time to clinical stability is defined as follows: time (days) until stable vital signs (16) for > 24h: Temperature < 37.8°C, heart rate/minute <100, spontaneous respiratory rate < 24 per minute, systolic blood pressure > 90mmHg mental status back to level before CAP, adequate oxygenation on room air of oxygen therapy (PaO2>60mmHg or pulse oxymetry > 90%). Blinded study personnel will check for clinical stability every 12 hours. Secondary Endpoints:- a) Mortality - b) Need for ICU stay - c) Side effects of corticosteroid treatment (i.e. rate of hyperglycemia, hypertension, nosocomial infections, recurrence, weight gain)- d) Value of adrenal function testing (ACTH test) and of prognostic hormonal biomarkers (e.g. total and free cortisol levels, copeptin, dehydroepiandrosterone (DHEA) as well as the ratio of cortisol to DHEA (4)) to identify those patients who benefit from corticosteroid treatment.- e) Effect of corticosteroid treatment on laboratory markers of infection, i.e. procalcitonin, C-reactive protein, interleukin and cytokine levels and on candidate genetic variants potentially associated with response. Working hypotheses for primary and secondary endpoints: 1.Use of corticosteroids will lead to a 25% relative risk reduction for death and clinical instability.2.Mortality rate will tend to decrease in the corticosteroid group as compared to placebo treatment.3.Need for ICU stay will tend to decrease in the corticosteroid group as compared to placebo treatment.4.Patients in the steroid group will have a higher rate of steroid induced hyperglycemia (as defined as fasting glucose level > 7mmol/L or postprandial glucose level > 11.1 mmol/L). Myopathy (as surrogate parameters urea and creatinine will be measured in plasma) and nosocomial infections will be similar in both groups.5.Adrenal function testing (i.e. 1ug ACTH test) will not be able to identifying those patients who benefit from corticosteroid treatment. Prognostic hormonal markers and the ratio of cortisol to DHEA will have a better accuracy to identify patients profiting from corticosteroid treatment. 6.Corticosteroid treatment will lead to a more rapid normalization of laboratory surrogates of infection, i.e. procalcitonin, C-reactive protein, interleukin levels and TNF-alpha.Significance:Data about corticosteroid use in patients with CAP are controversial and derive from small data sets. This large multicenter double-blind trial will give conclusive answers about risks and benefits of corticosteroid treatment in CAP.