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Background Fecal microbiota transfer (FMT) has become a standard of care in the prevention of multiple recurrent Clostridioides difficile (rCDI) infection. Aim While primary cure rates range from 70–80% following a single treatment using monodirectional approaches, cure rates of combination treatment remain largely unknown. Methods In a retrospective case-control study, outcomes following simultaneous bidirectional FMT (bFMT) with combined endoscopic application into the upper and lower gastrointestinal tract, compared to standard routes of application (endoscopy via upper or lower gastrointestinal tract and oral capsules; abbreviated UGIT, LGIT and CAP) on day 30 and 90 after FMT were assessed. Statistical matching partners were identified using number of recurrences ( Results Primary cure rates at D30 and D90 for bFMT were 100% (p=.001). The matched control groups showed cure rates of 81.3% for LGIT (p=.010), 62.5% for UGIT (p=.000) and 78.1% for CAP (p=.005) on D30 and 81.3% for LGIT (p=.010), 59.4% for UGIT (p=.000) and 71.9% for CAP (p=.001) on D90. Conclusion In our analysis, bFMT on the same day significantly increased primary cure rate at D30 and D90. These data require prospective confirmation but suggest that route of application may play a significant role in optimizing patient outcomes. ClinicalTrials.gov no: NCT02681068

INTRODUCTION: Fecal microbiota transfer (FMT) is highly effective in the treatment and prevention of recurrent Clostridioides difficile infection (rCDI) with cure rates of about 80% after a single treatment. Nevertheless, the reasons for failure in the remaining 20% remain largely elusive. The aim of the present study was to investigate different potential clinical predictors of response to FMT in Germany. METHODS: Information was extracted from the MicroTrans Registry (NCT02681068), a retrospective observational multicenter study, collecting data from patients undergoing FMT for recurrent or refractory CDI in Germany. We performed binary logistic regression with the following covariates: age, gender, ribotype 027, Eastern Co-operative Oncology Group score, immunosuppression, preparation for FMT by use of proton pump inhibitor, antimotility agents and bowel lavage, previous recurrences, severity of CDI, antibiotic induction treatment, fresh or frozen FMT preparation, and route of application. RESULTS: Treatment response was achieved in 191/240 evaluable cases (79.6%) at day 30 (D30) post FMT and 78.1% at day 90 (D90) post FMT. Assessment of clinical predictors for FMT failure by forward and confirmatory backward-stepwise regression analysis yielded higher age as an independent predictor of FMT failure (p = 0.001; OR 1.060; 95%CI 1.025–1.097). CONCLUSION: FMT in Germany is associated with high cure rates at D30 and D90. No specific pre-treatment, preparation or application strategy had an impact on FMT success. Only higher age was identified as an independent risk factor for treatment failure. Based on these and external findings, future studies should focus on the assessment of microbiota and microbiota-associated metabolites as factors determining FMT success.

Optimal management of infective endocarditis (IE) depends on the early detection of IE-causing pathogens and on appropriate antimicrobial and surgical therapy. The current guidelines of the European Society of Cardiology (ESC) recommend histopathological examination as the gold standard for diagnosing IE Habib et al. (Eur Heart J 30:2369-2413, 2005). We hypothesize that histopathological findings do not provide additional information relevant to clinical decision-making.We retrospectively reviewed a cohort of patients who had undergone surgery for native valve endocarditis (NVE) at the University Hospital Regensburg between September 1994 and February 2005. All episodes of intraoperatively confirmed endocarditis during this period were included in the study. Data were retrieved from surgical records, microbiological and histopathological reports, and medical files of the treating as well as admitting hospital. Pathogens were correlated with the site of manifestation of the affected heart valve and with clinical and histopathological findings.A total of 163 episodes of NVE were recorded and entered into our study for analysis. The valves affected were the aortic valve (45 %), the mitral valve (28 %), the aortic and mitral valve (22 %), and other valves (5 %). IE-causing pathogens were Staphylococcus aureus (22 %), viridans streptococci (18 %), enterococci (10 %), streptococci other than Streptococcus viridans (9 %), coagulase-negative staphylococci (5 %), miscellaneous pathogens (4 %), and culture-negative endocarditis (33 %). Infection with S. aureus was associated with high rates of sepsis, septic foci, and embolic events, while patients with enterococcal IE showed the highest rate of abscesses. Mortality rate in all subgroups was low without significant differences. However, histopathological findings correlated poorly with the pathogen involved and showed only few significant associations that were without clinical relevance.The clinical presentation of IE depends on the pathogen involved. Among the episodes of NVE examined, the histopathological examination of resected heart valves did not show any pathogen-specific morphological patterns and therefore did not provide any additional information of clinical value. Based on our findings, we recommend complementary cultures of the resected materials (valve tissue, thrombotic material, pacer wire) and implementation of molecular diagnostic methods (e.g., broad-range PCR amplification techniques) instead of histopathological analyses of resected valve tissue.

Lipoproteins modulate vascular cell function in inflammation. In this study, we analyzed whether plasma concentrations of lipoproteins and apolipoproteins in human sepsis are related to patient survival and the activation of blood monocytes and platelets. Observational study. Medical and surgical intensive care units (ICU) of a university hospital. 151 consecutive patients after sepsis criteria had been met for the first time. None. Plasma lipoproteins, apolipoproteins, platelet CD62P-expression, monocyte HLA-DR-expression, SAPS II-scores (Simplified Acute Physiology Score) and 30-day-mortality were recorded. Total cholesterol, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, apolipoprotein (apo)-AI and apo-B were all found to be significantly lower in non-survivors than in survivors. In contrast to other (apo)lipoproteins, apo-AI and HDL cholesterol further decreased in non-survivors during the ICU stay. Logistic regression analysis revealed apo-AI to be an independent predictor of 30-day-mortality. A significant inverse correlation was found for apo-AI/HDL-cholesterol and platelet activation. Later in the course of the disease, HLA-DR expression on monocytes correlated positively to apo-AI and apo-CI concentrations and inversely to the apo-E concentration. Low apo-AI is independently related to 30-day mortality in human sepsis and the decrease in apo-AI/HDL cholesterol correlates to increased platelet activation. Moreover, changes in apolipoproteins supposed to modulate lipopolysaccharide effects, such as apo-CI and apo-E, correlate to monocyte activation.

Blood cultures detect bacteremia in individual patients and help define local pathogen and resistance spectra. At the same time, the benefits of blood culture results in the management of individual patients – and therefore their cost–effectiveness – are disputed. During 1 calendar year, we conducted a prospective study of emergency department admissions with blood culture draws and at least a 3–day hospitalization afterwards. We prospectively surveyed treating physicians on usefulness of blood culture results for patient management. 428 diagnostic episodes (emergency visits) involving 390 patients occurred during the study period from 10/2002 to 10/2003. The analysis included 188/428 (44%) episodes with blood culture draws performed according to the predefined clinical standard where patients were hospitalized with sufficient duration. Absence of therapeutic consequences in response to blood culture results was reported for 138/142 (97%) of episodes with negative blood culture results, for 16/21 (76%) with blood culture results positive only for skin flora, and for 14/25 (56%) of episodes with blood cultures positive for obligate pathogens. Treating physicians regarded the blood culture results necessary for clarifying the etiology in 34/188 (18%) episodes, and rated blood culture results necessary for their therapeutic decisions in 29/188 (15%) episodes. Negative blood culture results rarely changed the management of medical inpatients. Our study suggests that in settings with broad–spectrum empirical antibiotic therapy positive blood culture results for obligate pathogens trigger adjustment of the antibiotic therapy in only about half of instances. Many blood cultures drawn in the emergency department where considered unnecessary by ward physicians. Guidelines for preventing unnecessary blood culture draws are warranted in order to increase the rate of their meaningful clinical consequences for medical inpatients initially treated with broad–spectrum empirical antibiotics.

Objective: Binding of bacterial cell wall components to CD14 and co-receptors on myeloid cells results in cellular activation and production of proinflammatory mediators. A recombinant anti-CD14 monoclonal antibody (IC14) has been shown to decrease lipopolysaccharide-induced responses in animal and human models of endotoxemia. This study was performed to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical pharmacology of IC14 in patients with severe sepsis.Design: Randomized, double-blind, placebo-controlled, dose-ranging, multiple-center trial.Setting: Six medical and surgical intensive care units located in Germany and the Netherlands.Patients: Forty patients with severe sepsis.Interventions: IC14 was administered intravenously to eight patients/cohort as single (1 mg/kg or 4 mg/kg) or multiple doses (4 mg/kg daily for 4 days, or 4 mg/kg on day I followed by 2 mg/kg daily for 3 days). A placebo group (two patients/cohort) was also included.Measurements and Main Results: The overall incidence and types of adverse events were similar among treatment groups. One patient in the group receiving multiple-dose IC14 4 mg/kg daily for 4 days experienced an anaphylactic reaction after receiving the first dose of study drug. IC14 did not induce antibody formation or increase the incidence of secondary bacterial infection. A mean IC14 serum concentration of approximately 1 mug/mL was required to achieve 50% of maximum membrane-bound CD14 receptor occupancy on peripheral blood monocytes. The pattern of proinflammatory and anti-inflammatory cytokines, chemokine, soluble receptor, soluble E-selectin, and acute phase proteins in response to treatment was highly variable by patient and IC14 treatment group.Conclusions: Single and multiple doses of IC14 were generally well tolerated and did not induce antibody formation or increase the incidence of secondary bacterial infection. The results suggest that CD14 blockade with IC14 warrants further clinical investigation to determine its ability to attenuate the proinflammatory response due to infection.

Recent data indicate that ceramide (Cer) and lysophosphatidylcholine (LPC) regulate immune cell functions. Since these bioactive lipids are generated in blood plasma by inflammatory lipases, we hypothesized that they may be involved in the process of acute systemic sepsis. In order to provide support for this hypothesis, we analyzed the plasma levels of Cer and LPC by quantitative tandem mass spectrometry in 102 sepsis patients starting with the day at which the sepsis criteria were fulfilled for the first time, as well as on day 4 and day 11. The values were compared with 56 healthy controls and correlated with sepsis-related mortality within 30 days of study entry. Most Cer species were increased in sepsis patients, while all LPC species were markedly decreased. In addition, we determined the molar ratios with their precursor molecules sphingomyelin (SPM) and phosphatidylcholine (PC), which reflect the enzymatic reactions responsible for their formation. Species-specific as well as total Cer-SPM ratios were increased, whereas LPC-PC ratios were decreased in sepsis patients. The increased Cer-SPM ratios as well as the decreased LPC-PC ratios showed a strong predictive power for sepsis-related mortality. Together with existing data from in vitro experiments and animal models, the results provide the first ex vivo indication for the role of Cer and lysophospholipids in systemic inflammation in humans.

Objective: In chronic inflammatory diseases, serum levels of dehydroepiandrosterone (DHEA) sulfate (DHEAS) are low. Interestingly, several non-inflammatory diseases display similarly low levels of DHEAS which points to other inhibitory factors such as an activated sympathetic nervous system (SNS) (e.g. in patients with heart failure, fibromyalgia, or cancer cachexia). We aimed to identify the influence of the SNS tone on stimulated adrenal steroid secretion in 16 male and 12 female healthy subjects. Methods: One group were given oral propranolol 2 h before a corticotropin-releasing hormone (CRH) test, and levels of adrenocorticotropin (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), androstenedione, DHEA, and DHEAS were measured. Results: Propranolol treatment decreased heart rate (by 20%), diastolic blood pressure (by 20%), and plasma ACTH, and increased serum cortisol, serum DHEAS, and the molar ratio of cortisol/17OHP, cortisol/DHEA, and DHEAS/DHEA similarly in female and male subjects. Conclusions :A b-adrenergic influence seems to decrease CRH-stimulated cortisol in relation to ACTH and 17OHP, and decreases DHEAS in relation to DHEA. Although other workers have found b-adrenergic stimulation of steroid secretion in cultured adrenocortical cells, the overall systemic influence of the SNS via b-adrenoceptors seems to inhibit adrenal steroids under unstimulated and stimulated conditions. Sympathetic hyperactivity may be a common denominator for low levels of DHEAS in inflammatory and non-inflammatory diseases. European Journal of Endocrinology 148 45–53

In two recent studies, we found autonomic nervous hyperreflexia in subjects with chronic inflammatory diseases, particularly, in those subjects with higher degrees of systemic inflammation. Since corticotropin-releasing factor (CRF) is induced by inflammatory stimuli and acts within the brain to change neuroendocrine and autonomic activity, we investigated CRF modulation of standard autonomic nervous reflexes. Fifteen healthy subjects were administered 100 μg CRF i.v., which led to a short-term increase of heart rate (p < 0.001) and a decrease in systolic and diastolic blood pressure (p < 0.050). These changes were accompanied by a reduction in heart rate variation at rest (p= 0.010) and during the respiratory sinus arrhythmia test (p= 0.019), and a reduction of pupillary latency time (p= 0.038). In further 21 normal subjects we studied the effect of prednisolone treatment on autonomic nervous function (100 mg/d during three days CRF reduction), which resulted in an increase of heart rate (p < 0.001), increase of heart rate variation during the respiratory sinus arrhythmia test (p < 0.001), increase in pupillary latency time (p= 0.012), a increase in maximal pupillary area (p= 0.002), and a decrease in diastolic blood pressure (p= 0.002). In conclusion, induction of a low central CRF content by prednisolone leads to a marked hyperreflexia in respiratory sinus arrhythmia and hyporeflexia in the latency time test. It is obvious that CRF can regulate autonomic reflexes. Possibly, central CRF status may also influence autonomic reflexes during chronic inflammation due to chronically changed central CRF concentration.

Eine Immunsuppression muss bei vielen Patienten in Kauf genommen werden – gleich ob bei der Behandlung von Autoimmun- oder rheumatischen Erkrankungen therapeutisch erwunscht oder als Nebeneffekt bei der Verhinderung der Transplantatabstosung oder bei der Behandlung von malignen Erkrankungen. Damit konnen jedoch Infektionen mit zum Teil seltenen, opportunistischen Erregern oder in einer durch den Immundefekt atypischen Prasentation verbunden sein, die diagnostische oder therapeutische Probleme bereiten. In dieser Ubersicht sollen daher bei nicht-neutropenischen Immunsupprimierten typischerweise auftretende Infektionen vorgestellt und Hinweise zu deren Diagnostik, Prophylaxe und Therapie gegeben werden.

Background: Patients receiving immunosuppressive therapy with corticosteroids and cytotoxic agents may develop opportunistic infections such as Pneumocystis carinii pneumonia (PCP). This indicates a severe T-cell defect, but so far there are no established criteria for identifying patients at risk. Patients and Methods: CD4+ and CD8+ T-lymphocyte counts were determined by flow cytometry in seven HIV-negative patients who developed PCP as a complication of immunosuppressive treatment. Results: CD4+ T-lymphocyte counts (T-helper phenotype) were less than 200/μl in all seven patients (mean 90.6/μl). The markedly reduced CD4 counts measured in these patients are similar to those observed in organ transplant recipients who developed PCP during immunosuppressive therapy for prevention of graft rejection and in HIV-positive patients with PCP as an AIDS-defining illness. Conclusion: Measuring CD4+ T-lymphocyte counts may be helpful in determining the risk of PCP not only in HIV-positive patients, but also in patients receiving immunosuppressive therapy. The risk of acqiring PCP seems to increase when CD4+ lymphocyte counts drop below 200/μl, regardless of the underlying disease.

A 46-year-old woman developed rapidly worsening renal insufficiency. Extensive calcification of the kidneys was found. The patient also suffered from ischaemic neuropathy, myopathy and arthritis. In a muscle biopsy multiple calcium oxalate crystals could be demonstrated surrounded by inflammatory infiltrates. Levels of oxalate in serum were markedly elevated. Diagnosis of primary hyperoxaluria type I was made by measuring alanine/glyoxylate aminotransferase activity in a liver biopsy. The patient underwent kidney transplantation twice, but each of the transplants failed after a very short time owing to hyperacute rejection and rupture of the organ, respectively. Eventually, combined liver/kidney transplantation was successfully performed. Two years after the transplantation, both organs work with good function. This case of primary hyperoxaluria type I is remarkable for the late onset of symptoms and the extensive involvement of other organ systems in addition to the kidneys. This case presentation confirms previous reports discouraging isolated kidney transplantation for patients with primary hyperoxaluria. Only combined liver/kidney transplantation can correct the metabolic defect and may give these patients superior long-term benefit.

Here, we report the case of fever of unknown origin (FUO) in a 77-year-old white man. The patient presented with a 3-week history of fever (between 38.5 and 39 degrees C) and general malaise. These symptoms had occurred about five to seven times during the past 30 years, and despite repeated hospitalizations, no diagnosis was made. Physical examination did not reveal any specific signs of infection nor did the patient fulfill the criteria for any rheumatic disease including vasculitides. Blood chemistry showed a greatly elevated C-reactive protein (CRP; 158.2 mg/l) and an erythrocyte sedimentation rate100 mm, indicating an active inflammatory process, and leukocytes were significantly elevated (20,000/mul). Rheumatological parameters showed only nonspecific changes. Finally, a 2-[(18)F]-fluoro-2-deoxy-D: -glucose-positron emission tomography was performed, revealing a markedly enhanced glucose uptake in the ascending aorta and the cardiac valves, indicating vasculitis as the cause of FUO in this patient. Based on this finding, treatment was started with corticosteroids, and 2 days after the initiation of treatment, the patient had normal body temperature, and after 5 days, CRP values had returned to normal. After tapering and final complete removal of steroid treatment, the patient was still free of symptoms, hence no disease-modifying antirheumatic drug therapy was necessary.

A 76-year-old white male presented with progressive malaise, weight loss and dyspnea at rest. Echocardiography revealed a circular pericardial effusion and global hypokinesia. Pericardiocentesis showed a purulent exudate and microbiologic examination revealed Mycobacterium bovis fully sensitive to isoniazid, streptomycin, ethambutol, rifampin, and pyrazinamide. By spoligotyping the isolate could be further differentiated to M. bovis ssp. caprae. Antimycobacterial therapy was initiated but 3 weeks later the patient's circulation and renal function deteriorated and he died with clinical signs of sepsis despite intensive care treatment. Pericarditis is a rare manifestation of tuberculosis and can be fatal even when diagnosed and treated appropriately. In low incidence countries diagnosis is often delayed and even overlooked.

This is a report of a 39-year-old patient diagnosed with seropositive rheumatoid arthritis at the age of 17. The patient died 2 years after the onset of extra-articular cardiac symptoms. This case demonstrates the devastating course of progressive constrictive pericarditis under sole medical therapy and emphasizes the importance of early radical pericardectomy to avoid progression of disease and secondary complications with fatal outcome. Further, we discuss risk factors, diagnostic caveats, diagnostic tests and therapy of hemodynamically relevant contrictive pericarditis.

Objectives. To determine the correlation between inflammatory cytokines and adrenal hormones in patients with polymyalgia rheumatica (PMR) and to compare the ratio of serum cortisol and androstenedione (ASD) or dehydroepiandrosterone sulphate (DHEAS ) in normal subjects with PMR patients. Methods. In 102 patients with PMR (32 beginning and 70 chronic disease) and 31 agematched and sex-matched healthy subjects, ASD, cortisol, DHEAS, interleukin-6 (IL-6), and tumour necrosis factor (TNF ) were measured by immunometric assays. Results. Serum levels of IL-6 were elevated in patients with PMR as compared with normal subjects (10.0 ± 1.6 vs 2.1 ± 0.1 pg/ml, P = 0.01), which was not found for TNF. In PMR patients, serum levels of IL-6 were positively correlated with serum levels of ASD (P < 0.001), cortisol (P < 0.001), and DHEAS (P = 0.038) irrespective of corticosteroid treatment. Serum levels of cortisol in relation to IL-6 were significantly lower in patients with chronic disease and long-standing corticosteroid administration as compared with patients with recent onset of the disease and without corticosteroid therapy (P < 0.01). Conclusions. In PMR, as expected, there was an increase in IL-6 serum levels that was associated with elevated serum levels of ASD, DHEAS, and cortisol which was more marked in patients with recent-onset disease and without corticosteroids. However, serum levels of cortisol in patients with and without corticosteroids were lower than expected by considering the inflammatory status (increased IL-6). This may indicate a change in the hypothalamic– pituitary–adrenal (HPA) axis responsiveness to inflammatory stimuli such as IL-6 during chronic disease. Furthermore, there seems to be a shift of biosynthesis to cortisol in relation to DHEAS or ASD in chronic disease. K : Polymyalgia rheumatica, Cortisol, Dehydroepiandrosterone sulphate, Androstenedione, Interleukin-6, Tumour necrosis factor.

The purpose of this article is to examine the prevalence, degree, and natural course of pupillary neuropathy (PANP), cardiovascular autonomic neuropathy (CANP), and sensorimotor neuropathy (SNP) and to study the impact of disease stage and medication on neuropathy in 61 consecutive patients with HIV. PANP, CANP, and SNP were assessed by standardized test procedures. Overall prevalence of PANP, CANP, and SNP were 66%, 15%, and 15%, respectively. The maximal pupillary area (pupillary measure, p

In chronic inflammatory diseases, cytokines stimulate the hypothalamus pituitary adrenal axis and the hypothalamus autonomic nervous system (HANS) axis. The present study was performed to find autonomic nervous function parameters in patients with systemic lupus erythematosus (SLE) which are suitable to demonstrate the activation of the HANS axis during systemic inflammation. Thirty-four patients with SLE (age 35.3 +/- 1.9 yr) were investigated by seven standardized autonomic nervous function tests. The SLEDAI and laboratory parameters of systemic inflammation were assessed by standard techniques. Pupillary latency time hyperreflexia was found in 29.4%, whereas maximal pupillary area was hyperresponsive in only 2.9%. A total of 12% had overall cardiovascular autonomic nervous hyperreflexia. Patients with latency time hyperreflexia had more severe systemic inflammation [erythrocyte sedimentation rate (ESR): P < 0.001; C-reactive protein (CRP): P = 0.0094; fibrinogen: P < 0.001; albumin: P = 0.003; antinuclear antibodies: P = 0.020]. The longitudinal study of 13 patients during 4 yr demonstrated a parallel increase and decrease in latency time percentile and ESR. SLE patients with increased systemic inflammation had an activated HANS axis which can be measured by a parasympathetic pupillary reflex test.