No description available.

Systemische Inflammation (SIRS) und Sepsis sind bekannte postoperative Komplikationen nach kardiochirurgischen Eingriffen. Bei 77,1 % der untersuchten 3653 kardiochirurgischen Patienten bestanden am ersten postoperativen Tag definierte Symptome eines SIRS. Nur 20 % dieser Patienten entwickelten ein prolongiertes SIRS über mindestens die ersten 72 Stunden postoperativ und 4,4 % eine Sepsis im weiteren primären intensivmedizinischen Verlauf. Aus der Patientengruppe mit prolongiertem SIRS entwickelten immerhin 21,8 % eine Sepsis. Die 564 Patienten mit prolongiertem SIRS waren durch eine signifikant (p< 0,001) verlängerte Beatmungs- und Behandlungsdauer auf der Intensivstation (ICU), eine erhöhte Krankenhausliegedauer sowie eine um den Faktor 10 signifikant erhöhte ICU- und Krankenhausmortalität im Vergleich zu Patienten ohne prolongiertes SIRS gekennzeichnet. Die 135 Patienten mit einer Sepsis während ihrer primären postoperativen intensivstationären Behandlung hatten eine deutlich erhöhte intensivstationäre Mortalität von 40,7 % gegenüber 1,6 % bei Patienten ohne Sepsis. Die Patienten mit prolongiertem SIRS (15,4 % der Gesamtpopulation) benötigten insgesamt 52,9 % der Bettentage und 57,7 % der Gesamtkosten der intensiv-medizinischen Behandlung. Die septischen Patienten (3,7 %) verursachten alleine 24,6 % der intensivstationären Behandlungstage sowie 28,7 % der Gesamtkosten. Die fünf Variablen weibliches Geschlecht, das Auftreten definierter intraoperativer Komplikationen, ein APACHE II- Score > 17 bei Aufnahme auf der Intensivstation, der postoperative Bedarf von mehr als einem Inotropikum sowie das Vorhandensein von definierten, therapiebedürftigen metabolischen Störungen innerhalb der ersten 24 Stunden postoperativ diskriminierten in Bezug auf das Vorhandensein oder Nicht-Vorhandensein der Zielvariablen prolongiertes SIRS (> 3 Tage ) mehr als 88 % der Patienten richtig. Jeweils über 96 % der Patienten konnten durch die aus diesen Variablen entwickelten Regressionsgleichungen richtig zugeordnet werden bezüglich des Auftretens oder Nicht-Auftretens einer Sepsis bzw. eines letalen Ausgangs. Das intern validierten Modell für die Zielvariable prolongiertes SIRS (> 3 Tage) erreichte eine hohe Spezifität von über 97 % bei einer Sensitivität von 39 %. Die vorliegenden Regressionsgleichungen ermöglichen es somit, am Patientengut dieser Institution prospektiv Patienten mit erhöhtem Risiko auf ein prolongiertes SIRS bzw. eine Sepsis mit hoher Spezifität zu selektionieren. / The development of a systemic inflammatory response syndrome (SIRS) and sepsis are well known complications after cardiac surgery. In the present study, 77.1 % of the 3653 cardiac surgical patients developed SIRS or SIRS-like symptoms on the first postoperative day. Only 20 % of these patients, however, showed a prolonged SIRS during the first 3 postoperative days. 4.4 % of all patients had septic complications during their stay on the intensive care unit (ICU). However, 21.8 % of the patients with prolonged SIRS developed sepsis. The identified 564 patients with prolonged SIRS showed a significantly (p < 0.001) increased duration of mechanical ventilation, ICU- and hospital treatment, respectively. Their ICU- and hospital mortality was tenfold higher than in patients without prolonged SIRS. The ICU-mortality of 135 septic patients was 40.7 % in contrast to 1.6 % in patients without sepsis. Patients with prolonged SIRS (15.4 % of the study population) accounted for 52.9 % of the bed days on ICU and for 57.7 % of the total costs. Septic patients (3.7 % of the study population) required 24.6 % of the bed days and 28.7 % of the total costs during their ICU-stay. The use of 5 variables including female gender, defined intraoperative complications, an APACHE II- Score of > 17 on ICU-admission, the use of more than one inotrope postoperatively, and the treatment of defined metabolical disorders identified 88 % of the patients with prolonged SIRS (> 3 days) correctly during the first 24 hours postoperativly. The resulting predictive models identified more than 96 % of the patients with sepsis or lethal outcome correctly. The internal validation of the predictive model for prolonged SIRS (> 3 days) demonstrated a specifity of 97 % and a sensitivity of 39 %. Therefore, the early identification of patients at risk for the development of prolonged SIRS or sepsis in our institution seems to be possible using multiple logistic regression of these predictive models.

Myocardial infarction is a leading cause of morbidity and mortality worldwide. The purpose of this thesis was to develop strategies for the assessment of patients with suspected myocardial infarction using a high-sensitivity cardiac troponin I assay, and to evaluate the relationship between the aetiology of myocardial infarction and long term clinical outcomes to identify opportunities to modify outcomes. In the United Kingdom, approximately 1 million patients present to hospital with chest pain each year and are assessed for suspected myocardial infarction, yet fewer than 20% of patients receive this diagnosis. Prior clinical standards mandated the admission of patients for serial cardiac troponin testing to identify myocardial necrosis and determine if myocardial infarction had occurred. However, new high-sensitivity assays offer a magnitude improvement in diagnostic precision, and as such provide a novel approach to diagnose or exclude myocardial infarction at an earlier stage. In our first study, I evaluate the performance of a high-sensitivity cardiac troponin I assay as a risk stratification tool in patients with suspected acute coronary syndrome. A systematic review and individual patient-level data meta-analysis was performed, including prospective studies measuring high-sensitivity cardiac troponin I in patients with suspected acute coronary syndrome, where the diagnosis was adjudicated according to the universal definition of myocardial infarction. The primary outcome was myocardial infarction or cardiac death during the index hospitalization or at 30 days. Meta-estimates for primary and secondary outcomes were derived using a binomial-normal random effects model. Performance was evaluated in subgroups and across a range of troponin concentrations (2-16 ng/L) using individual patient data. A total of 22,457 patients were included in the meta-analysis (age 62 [15.5] years; n=9,329 (41.5%) women), of whom 2,786 (12.4%) experienced myocardial infarction or cardiac death at 30 days. Cardiac troponin I concentrations were < 5 ng/L at presentation in 11,012 (49%) patients, with a negative predictive value of 99.5% (95% confidence interval [CI] 99.3-99.6) for myocardial infarction or cardiac death at 30 days. Lower thresholds did not improve safety, but did significantly reduce the proportion identified as low risk. This threshold of 5 ng/L formed the basis for the development of a diagnostic pathway for patients with suspected acute coronary syndrome. In a cohort study of 1,218 patients with suspected acute coronary syndrome who underwent high-sensitivity cardiac troponin I measurement at presentation, 3 and 6 or 12 hours, I derived and validated a novel pathway (rule out myocardial infarction if < 5 ng/L at presentation, or change < 3 ng/L and < 99th centile at 3 hours), and compared this with the established European Society of Cardiology 3-hour pathway (rule out myocardial infarction if < 99th centile at presentation, or at 3 hours if symptoms < 6 hours). The primary outcome was a comparison of the negative predictive value (NPV) of both pathways for myocardial infarction or cardiac death at 30 days. The primary outcome was evaluated in pre-specified subgroups stratified by age, gender, time of symptom onset and known ischaemic heart disease. In those < 99th centile at presentation, the ESC pathway ruled out myocardial infarction in 28.1% (342/1,218) and 78.9% (961/1,218) at presentation and 3 hours respectively, missing 18 index and two 30-day events (NPV 97.9%, 95% confidence intervals [CI] 96.9-98.7%). The novel pathway ruled out 40.7% (496/1,218) and 74.2% (904/1,218) at presentation and 3 hours, missing two index and two 30-day events (NPV 99.5%, 95% CI 99.0-99.9%; P < 0.001 for comparison). The NPV of the novel pathway was greater than the ESC pathway overall (P < 0.001), and in all subgroups including those presenting early or known to have ischaemic heart disease. There are a number of additional approaches for the rule out of myocardial infarction. Clinical risk scores apply conventional risk factors to estimate the probability of myocardial infarction. The most widely implemented scores, HEART, EDACS, GRACE and TIMI, have been extensively validated when used alongside contemporary troponin assays, however, their impact on pathways applying high-sensitivity cardiac troponin testing is less clear. In 1,935 patients with suspected acute coronary syndrome, I evaluated the safety and efficacy of our novel pathway or the European Society of Cardiology 3-hour pathway alone, or in conjunction with low-risk TIMI (0 or 1), GRACE (≤108), EDACS (< 16) or HEART (≤3) scores. Myocardial infarction or cardiac death at 30-days occurred in 14.3% (276/1,935). The ESC pathway ruled out 70% with 27 missed events giving a negative predictive value (NPV) of 97.9% (95% confidence interval [CI], 97.1 to 98.6%). Addition of a HEART score ≤3 reduced the proportion ruled out by the ESC pathway to 25%, but improved the NPV to 99.7% (95%CI 99.0 to 100%, P < 0.001). The novel pathway ruled out 65% with three missed events for a NPV of 99.7% (95%CI 99.4 to 99.9%). No risk score improved the NPV, but all reduced the proportion ruled out (24-47%, P < 0.001 for all). Whilst myocardial infarction due to atherosclerotic plaque rupture and thrombosis (type 1) is well described, the natural disease course of myocardial infarction due to oxygen supply-demand imbalance without atherothrombosis (type 2) is poorly understood. I aimed to define long-term outcomes and explore risk stratification in patients with type 2 myocardial infarction and myocardial injury. Consecutive patients (n=2,122) with elevated cardiac troponin I concentrations (≥0.05 μg/L) were identified at a tertiary cardiac centre. All diagnoses were adjudicated as per the Universal Definition of Myocardial Infarction. The primary outcome was all-cause death. Secondary outcomes included major adverse cardiovascular events (MACE; non-fatal myocardial infarction or cardiovascular death) and non-cardiovascular death. To explore competing risks, cause-specific hazard ratios were obtained using Cox regression models. The adjudicated index diagnosis was type 1 or type 2 myocardial infarction or myocardial injury in 1,171 (55.2%), 429 (20.2%) and 522 (24.6%) patients, respectively. At five years, all-cause death rates were higher in those with type 2 myocardial infarction (62.5%) or myocardial injury (72.4%) compared with type 1 myocardial infarction (36.7%). The majority of excess deaths in those with type 2 myocardial infarction or myocardial injury were due to non-cardiovascular causes (HR 2.32, 95%CI 1.92-2.81, versus type 1 myocardial infarction). Despite this, the observed crude MACE rates were similar between groups (30.6% versus 32.6%), with differences apparent after adjustment for co-variates (HR 0.82, 95%CI 0.69-0.96). Coronary heart disease was an independent predictor of MACE in those with type 2 myocardial infarction or myocardial injury (HR 1.71, 95%CI 1.31-2.24). Patients with type 2 myocardial infarction were less likely to receive secondary prevention therapy, suggesting a treatment gap may exist and there may be potential to modify clinical outcomes. A risk stratification threshold has been defined using high-sensitivity cardiac troponin I which identifies patients at very low risk of myocardial infarction or cardiac death. A diagnostic pathway incorporating this risk stratification threshold appears safer than established guidelines which apply the 99th centile alone. The use of clinical risk scores does not appear to improve the safety of this approach, however, does significantly reduce efficacy. Overall, these findings demonstrate the potential of high-sensitivity cardiac troponin testing to improve the efficiency of the assessment of patients with suspected acute coronary syndrome without compromising patient safety. The observations in those with myocardial injury and infarction have identified a phenotype of patients with type 2 myocardial infarction and coronary artery disease who are at increased cardiovascular risk, and who may benefit from targeted secondary prevention. The studies presented will inform the design of future clinical trials, and may inform international guidelines for the assessment of patients with suspected acute coronary syndrome.

<p>In unstable coronary artery disease (CAD) it still is a matter of debate which patients should undergo early revascularisation. In the FRISC II study (n=2457) an early invasive strategy was, compared to a primarily non-invasive strategy, associated with reduced mortality and myocardial infarction (MI) rates. However, in this heterogeneous group of patients, tools for an appropriate selection to revascularisation are needed.</p><p>From the FRISC II study we evaluated the prognosis, the angiographic extent of CAD and the effects of an early invasive strategy in relation to risk variables on admission.</p><p>The occurrence of ST depression and/or elevated levels of Troponin T were associated with a higher risk for death and MI, more severe CAD and also with a reduction of death or MI by the early invasive strategy.</p><p>Elevated levels of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (Il-6) were associated with a higher mortality but an unchanged MI rate. Elevated levels of Il-6, but not CRP, identified patients with a large reduction of mortality by the invasive strategy.</p><p>Age ≥ 70 years, male gender, diabetes, previous MI, ST depression and elevated levels of troponin and markers of inflammation were independently associated with an adverse outcome. The FRISC-score was constructed using these 7 variables. At FRISC-score ≥ 5 an early invasive strategy markedly reduced mortality and MI, at FRISC–score 3-4 death/MI was reduced, whereas in patients with a FRISC-score 0-2 neither mortality nor death/MI was influenced.</p><p>In unstable CAD, a non-invasive strategy seems justified only for patients at low risk, i.e. FRISC score < 2. In patients with intermediate and high risk, i.e. FRISC-score ≥ 3, an early invasive strategy is recommended.</p>

In unstable coronary artery disease (CAD) it still is a matter of debate which patients should undergo early revascularisation. In the FRISC II study (n=2457) an early invasive strategy was, compared to a primarily non-invasive strategy, associated with reduced mortality and myocardial infarction (MI) rates. However, in this heterogeneous group of patients, tools for an appropriate selection to revascularisation are needed. From the FRISC II study we evaluated the prognosis, the angiographic extent of CAD and the effects of an early invasive strategy in relation to risk variables on admission. The occurrence of ST depression and/or elevated levels of Troponin T were associated with a higher risk for death and MI, more severe CAD and also with a reduction of death or MI by the early invasive strategy. Elevated levels of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (Il-6) were associated with a higher mortality but an unchanged MI rate. Elevated levels of Il-6, but not CRP, identified patients with a large reduction of mortality by the invasive strategy. Age ≥ 70 years, male gender, diabetes, previous MI, ST depression and elevated levels of troponin and markers of inflammation were independently associated with an adverse outcome. The FRISC-score was constructed using these 7 variables. At FRISC-score ≥ 5 an early invasive strategy markedly reduced mortality and MI, at FRISC–score 3-4 death/MI was reduced, whereas in patients with a FRISC-score 0-2 neither mortality nor death/MI was influenced. In unstable CAD, a non-invasive strategy seems justified only for patients at low risk, i.e. FRISC score &lt; 2. In patients with intermediate and high risk, i.e. FRISC-score ≥ 3, an early invasive strategy is recommended.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22303号 / 医博第4544号 / 新制||医||1040(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 福原 俊一, 教授 川口 義弥, 教授 松村 由美 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Hintergrund: Die ambulant erworbene Pneumonie (CAP) ist bei Patienten mit schwerer Immunsuppression häufig und mit einer schlechten Prognose assoziiert. Scores zur Risikoprädiktion bei Sepsis oder CAP sind bei diesen Patienten kaum untersucht. Fragestellung: Ziel der Studie war die Evaluation der prognostischen Prädiktion der qSOFA- und CRB-65-Scores bei Patienten mit Pneumonie und schwerer Immunsuppression. Methoden: Es handelt sich um eine retrospektive Kohortenstudie am Uniklinikum Dresden zwischen 2014 und 2017 mit Einschluss konsekutiver Patienten mit CAP und schwerer Immunsuppression (u.a. Neutropenie, aktive hämatologische Neoplasie, Z.n. allogener Stammzell- oder Organtransplantation, HIV–Infektion mit CD4-Zellen < 200/µl, zytostatische oder rheumatologische immunsuppressive Therapie innerhalb der letzten 3 Monate, Prednisolon-Äquivalent >10mg/d > 3 Monate). Patienten mit dokumentierter Therapielimitation oder direkter Aufnahme auf die Intensivstation wurden ausgeschlossen. Die CRB-65- und qSOFA-Kriterien wurden bei Erstvorstellung dokumentiert. Der primäre Endpunkt war definiert als Notwendigkeit mechanischer Beatmung oder von Vasopressoren (MVVS) und/oder Krankenhausletalität. Um die prognostischen Eigenschaften der Scores, der einzelnen Score- Parameter, sowie der darüber hinaus erhobenen Parameter zu untersuchen, wurden univariate und multivariate Regressionsanalysen sowie ROC-Kurvenanalysen durchgeführt. Ergebnisse: Von 198 eingeschlossenen Patienten erfüllten 41 (21%) den primären Endpunkt, 19 (10%) verstarben. Das Alter war kein unabhängiger Prädiktor, dagegen waren sowohl der CRB- als auch der qSOFA-Score in der Kaplan-Meier-Analyse sowie in der multivariaten Analyse unabhängig von anderen Prädiktoren mit dem primären Endpunkt assoziiert (jeweils p < 0.001). In der ROC-Analyse erreichten beide Scores eine moderate Prädiktion (AUC 0,70 bzw. 0,69), bei 0 vorliegenden Kriterien zeigte sich ein NPV von jeweils 89% (13/120 bzw. 12/105 Patienten „übersehen“). Bei ≥ 2 Kriterien resultierten PPVs von 44 bzw. 58%. Diskussion: Sowohl die CRB- als auch die qSOFA-Kriterien zeigten eine moderate, aber signifikante prognostische Aussagekraft. Das Alter ist dagegen in dieser Population kein geeigneter prädiktiver Parameter. Auch bei den Scores ohne Alterskriterium ist der NPV jedoch nicht ausreichend zum Ausschluss von Komplikationen. Daher sollten alle schwer immunsupprimierten Patienten mit Pneumonie zumindest initial stationär, bei > 1 positivem Score-Kriterium auch intensiv hinsichtlich einer akuten Organdysfunktion, überwacht werden.:ABBILDUNGSVERZEICHNIS V TABELLENVERZEICHNIS VI ABKÜRZUNGS- UND SYMBOLVERZEICHNIS VIII 1 EINLEITUNG 1 1.1 DIE AMBULANT ERWORBENE PNEUMONIE 1 1.1.1 Definition und Einteilung 1 1.1.2 Epidemiologie 2 1.1.3 Diagnosestellung 3 1.1.4 Erregerspektrum bei CAP ohne Immunsuppression 4 1.1.5 Therapie der CAP ohne Immunsuppression 5 1.1.6 Verlauf, klinische Stabilitätskriterien und Therapiedauer 6 1.2 RISIKOSTRATIFIZIERUNG DER CAP OHNE IMMUNSUPPRESSION 7 1.2.1 Bedeutung der korrekten und schnellen Risikostratifizierung 7 1.2.2 Risikostratifizierung der CAP ohne Immunsuppression 8 1.2.3 Aktuelle Studien zur Risikostratifizierung mittels CRB-65/qSOFA 13 1.3 CAP BEI IMMUNSUPPRESSION 15 1.3.1 Aufbau des Immunsystems 15 1.3.2 Immunsuppression 16 1.3.3 Ursachen der Immunsuppression 17 1.3.4 Bedeutung der CAP bei Immunsuppression 19 1.3.5 Verändertes Erregerspektrum und Therapie bei CAP-Patienten mit Immunsuppression 20 1.3.6 Risikostratifizierung bei CAP und Immunsuppression 23 1.4 RATIONALE UND STUDIENZIEL 26 2 METHODEN 28 2.1 ÜBERBLICK 28 2.2 STUDIENDESIGN 28 2.3 SELEKTION DER STUDIENPOPULATION 28 2.3.1 Datenbasis 28 2.3.2 Einschlusskriterien 29 2.3.3 Ausschlusskriterien 30 2.3.4 Studienpopulation 31 2.4 ENDPUNKTE 33 2.5 DATENERFASSUNG 33 2.5.1 Erhobene Parameter 33 2.5.2 Berechnete Scores und Parameter 34 2.6 FALLZAHLSCHÄTZUNG 34 2.7 STATISTISCHE ANALYSE 34 3 ERGEBNISSE 36 3.1 PATIENTENCHARAKTERISTIKA 36 3.2 MIKROBIOLOGIE 39 3.3 UNIVARIATE ANALYSEN 41 3.3.1 Primärer Endpunkt 41 3.3.2 Sekundärer Endpunkt 45 3.4 MULTIVARIATE ANALYSEN 48 3.5 KAPLAN-MEIER-ANALYSE 54 3.6 ROC-KURVENANALYSE FÜR QSOFA-, CRB-65-, QSOFA-65- UND CRB- SCORE 56 4 DISKUSSION 61 4.1 WICHTIGSTE ERGEBNISSE DER ARBEIT 61 4.2 REPRÄSENTATIVITÄT DER PATIENTENKOHORTE 61 4.2.1 Patientencharakteristika 61 4.2.2 Mikrobiologie 65 4.2.3 Endpunkte 66 4.3 PRÄDIKTIVE PARAMETER 67 4.3.1 CRB-65-Einzelkriterien und -Score 67 4.3.2 qSOFA-Einzelkriterien und -Score 69 4.3.3 Neuer Score 70 4.3.4 qSOFA-Score und CRB-65-Score im direkten Vergleich 70 4.3.5 Komorbiditäten 71 4.3.6 Laborchemische Prognoseparameter 72 4.3.7 Weitere Prognoseparameter 73 4.4 LIMITATIONEN 75 4.5 SCHLUSSFOLGERUNG UND KLINISCHE BEDEUTUNG 75 4.6 AUSBLICK 77 5 ZUSAMMENFASSUNG 78 6 SUMMARY 79 7 LITERATURVERZEICHNIS 80 8 ANHANG 93 9 DANKSAGUNG 101 10 SELBSTSTÄNDIGKEITSERKLÄRUNG 102 / Background: Community-acquired pneumonia (CAP) in immunocompromised patients is a common issue and often associated with poor prognosis. Scores for risk prediction used in immunocompetent patients with sepsis or CAP are poorly evaluated for these patients. Aim: The purpose of the study was to evaluate the prognostic value of the qSOFA- and CRB-65-criteria for risk stratification of immunocompromised patients with CAP. Methods: The retrospective cohort study including 198 consecutive patients hospitalized in the university hospital of Dresden with CAP and severe immunosuppression (neutropenia, active haematological neoplasia, stem cell transplantation, solid organ transplantation, HIV-infection with CD4-cells < 200/µl, immunosuppressive treatment within the last 3 months, prednisolone equivalent > 10 mg/d > 3 months) was conducted between 2014 and 2017. Patients that were admitted directly to the intensive care unit and those with treatment restrictions were excluded. The CRB- and qSOFA-criteria were documented when patients entered the emergency department. Primary outcome was defined as need of mechanical ventilation (MV) or vasopressor support (VS) and/or hospital-mortality. Univariate and multivariate regression analysis as well as ROC curve analysis were performed to investigate the prognostic properties of all scores, the single score parameters and other predictive parameters. Results: 41 (21 %) of 198 included patients reached the primary endpoint and 19 (10 %) of the patients died. Age was not an independent predictive parameter. Using Kaplan-Meier and multivariate logistic regression analysis, both the CRB- and qSOFA-scores were independently associated with the primary endpoint (each p < 0,001). However, after ROC curve analysis both scores only showed moderate prediction (AUC 0,70 and 0,69). With a score of 0, the negative predictive value (NVP) was about 89% in both scores (13/120 and 12/105 missed patients, respectively). When 2 or more parameters were positive the positive predictive values (PPV) were 44 and 58%, respectively. Conclusion: Both, the qSOFA as well as the CRB score, showed moderate but significant prognostic properties. In this population, age was an inappropriate predictive parameter. Even without the age criterion the NPV was inadequate to exclude the possibility of organ failure and complications. Therefore, all immunocompromised patients, especially those with a score > 1, should be monitored intensively concerning organ failure when having a CAP.:ABBILDUNGSVERZEICHNIS V TABELLENVERZEICHNIS VI ABKÜRZUNGS- UND SYMBOLVERZEICHNIS VIII 1 EINLEITUNG 1 1.1 DIE AMBULANT ERWORBENE PNEUMONIE 1 1.1.1 Definition und Einteilung 1 1.1.2 Epidemiologie 2 1.1.3 Diagnosestellung 3 1.1.4 Erregerspektrum bei CAP ohne Immunsuppression 4 1.1.5 Therapie der CAP ohne Immunsuppression 5 1.1.6 Verlauf, klinische Stabilitätskriterien und Therapiedauer 6 1.2 RISIKOSTRATIFIZIERUNG DER CAP OHNE IMMUNSUPPRESSION 7 1.2.1 Bedeutung der korrekten und schnellen Risikostratifizierung 7 1.2.2 Risikostratifizierung der CAP ohne Immunsuppression 8 1.2.3 Aktuelle Studien zur Risikostratifizierung mittels CRB-65/qSOFA 13 1.3 CAP BEI IMMUNSUPPRESSION 15 1.3.1 Aufbau des Immunsystems 15 1.3.2 Immunsuppression 16 1.3.3 Ursachen der Immunsuppression 17 1.3.4 Bedeutung der CAP bei Immunsuppression 19 1.3.5 Verändertes Erregerspektrum und Therapie bei CAP-Patienten mit Immunsuppression 20 1.3.6 Risikostratifizierung bei CAP und Immunsuppression 23 1.4 RATIONALE UND STUDIENZIEL 26 2 METHODEN 28 2.1 ÜBERBLICK 28 2.2 STUDIENDESIGN 28 2.3 SELEKTION DER STUDIENPOPULATION 28 2.3.1 Datenbasis 28 2.3.2 Einschlusskriterien 29 2.3.3 Ausschlusskriterien 30 2.3.4 Studienpopulation 31 2.4 ENDPUNKTE 33 2.5 DATENERFASSUNG 33 2.5.1 Erhobene Parameter 33 2.5.2 Berechnete Scores und Parameter 34 2.6 FALLZAHLSCHÄTZUNG 34 2.7 STATISTISCHE ANALYSE 34 3 ERGEBNISSE 36 3.1 PATIENTENCHARAKTERISTIKA 36 3.2 MIKROBIOLOGIE 39 3.3 UNIVARIATE ANALYSEN 41 3.3.1 Primärer Endpunkt 41 3.3.2 Sekundärer Endpunkt 45 3.4 MULTIVARIATE ANALYSEN 48 3.5 KAPLAN-MEIER-ANALYSE 54 3.6 ROC-KURVENANALYSE FÜR QSOFA-, CRB-65-, QSOFA-65- UND CRB- SCORE 56 4 DISKUSSION 61 4.1 WICHTIGSTE ERGEBNISSE DER ARBEIT 61 4.2 REPRÄSENTATIVITÄT DER PATIENTENKOHORTE 61 4.2.1 Patientencharakteristika 61 4.2.2 Mikrobiologie 65 4.2.3 Endpunkte 66 4.3 PRÄDIKTIVE PARAMETER 67 4.3.1 CRB-65-Einzelkriterien und -Score 67 4.3.2 qSOFA-Einzelkriterien und -Score 69 4.3.3 Neuer Score 70 4.3.4 qSOFA-Score und CRB-65-Score im direkten Vergleich 70 4.3.5 Komorbiditäten 71 4.3.6 Laborchemische Prognoseparameter 72 4.3.7 Weitere Prognoseparameter 73 4.4 LIMITATIONEN 75 4.5 SCHLUSSFOLGERUNG UND KLINISCHE BEDEUTUNG 75 4.6 AUSBLICK 77 5 ZUSAMMENFASSUNG 78 6 SUMMARY 79 7 LITERATURVERZEICHNIS 80 8 ANHANG 93 9 DANKSAGUNG 101 10 SELBSTSTÄNDIGKEITSERKLÄRUNG 102

No description available.

The ability to detect residual levels of leukemic blasts (measurable residual disease, MRD) has already been integrated in the daily routine for treatment of patients with chronic myeloid and acute lymphoblastic leukemia. In acute myeloid leukemia (AML), a variety of mostly retrospective studies have shown that individuals in AML remission who tested positive for MRD at specific time-points or had increasing MRD levels are at significantly higher risk of relapse and death compared to MRD-negative patients. However, these studies differ with respect to the “MRD-target”, time-point of MRD determination, material analyzed, and method applied. How this probably very valuable MRD information in individual patients may be adapted in the daily clinical routine, e.g., to separate patients who need more aggressive therapies from those who may be spared additional—potentially toxic—therapies is still a work-in-progress. With the exception of MRD assessment in acute promyelocytic leukemia (APL), the lack of randomized, prospective trials renders MRD-based decisions and clinical implications in AML a difficult task. As of today, we still do not have proof that early intervention in MRD-positive AML patients would improve outcomes, although this is very likely. In this article, we review the current knowledge on non-APL AML MRD assessment and possible clinical consequences.