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Recently, unexpectedly high virus-specific IgG4 levels were reported after more than two mRNA vaccinations. Class switch towards IgG4 occurs after long-term antigen exposure, downregulates immune responses and is associated with several autoimmune diseases.Here, we examined differences in antigen-specific IgG subtypes in serum samples from 64 Post-COVID patients and an equally sized cohort of convalescent controls.In both cohorts, the relative amounts of spike protein-specific IgG subtypes were comparable. IgG1 was the most frequent, followed by IgG3, IgG2, and IgG4. A difference between cohorts was observed only for IgG2, which was significantly lower in the Post-COVID cohort. Further analysis of the reactive IgG4 revealed a small but significant difference for the spike protein receptor-binding domain but not for the spike ectodomain.Since the total IgG4 levels are very low, we do not expect a biologically relevant role in Post-COVID syndrome. However, reduced virus-specific IgG2 levels could contribute to the persistence of SARS-CoV-2, causing chronic inflammation in the setting of Post-COVID syndrome.

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

Objective To follow serological immune responses of front-line healthcare workers after PCR-confirmed COVID-19 for a mean of 30 weeks, describe the time-course of SARS-CoV-2 spike protein-specific IgG, IgA and IgM levels and to identify associations of the immune response with symptoms, demographic parameters and severity of disease. Methods Anti-SARS-CoV-2 S protein-specific IgG, IgA and IgM antibodies were measured at three time points during the 30-week follow-up. COVID-19-specific symptoms were assessed with standardized questionnaires. Results 95% of the participants mounted an IgG response with only modest decline after week 12. IgG-type antibodies were still detectable in almost 90% of the subjects at 30 weeks. IgA and IgM responses were less robust and antibody titers decreased more rapidly. At 30 weeks, only 25% still had detectable IgA-type and none had IgM-type antibodies. Higher age and higher disease severity were independently associated with higher IgG antibody levels, albeit with wide variations. Conclusion Serological immune responses after COVID-19 show considerable inter-individual variability, but show an association with increasing age and higher severity of disease. IgG-type anti-SARS-CoV-2 antibodies remain positive in 90% of the individuals 30 weeks after onset of symptoms.

ObjectiveThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic challenges national health systems and the global economy. Monitoring of infection rates and seroprevalence can guide public health measures to combat the pandemic. This depends on reliable tests on active and former infections. Here, we set out to develop and validate a specific and sensitive enzyme linked immunosorbent assay (ELISA) for detection of anti-SARS-CoV-2 antibody levels.MethodsIn our ELISA, we used SARS-CoV-2 receptor-binding domain (RBD) and a stabilized version of the spike (S) ectodomain as antigens. We assessed sera from patients infected with seasonal coronaviruses, SARS-CoV-2 and controls. We determined and monitored IgM-, IgA- and IgG-antibody responses towards these antigens. In addition, for a panel of 22 sera, virus neutralization and ELISA parameters were measured and correlated.ResultsThe RBD-based ELISA detected SARS-CoV-2-directed antibodies, did not cross-react with seasonal coronavirus antibodies and correlated with virus neutralization (R2 = 0.89). Seroconversion started at 5 days after symptom onset and led to robust antibody levels at 10 days after symptom onset. We demonstrate high specificity (99.3%;N = 1000) and sensitivity (92% for IgA, 96% for IgG and 98% for IgM; > 10 days after PCR-proven infection;N = 53) in serum.ConclusionsWith the described RBD-based ELISA protocol, we provide a reliable test for seroepidemiological surveys. Due to high specificity and strong correlation with virus neutralization, the RBD ELISA holds great potential to become a preferred tool to assess thresholds of protective immunity after infection and vaccination.

Background The long-term course of immunity among individuals with a history of COVID-19, in particular among those who received a booster vaccination, has not been well defined so far. Methods SARS-CoV-2-specific antibody levels were measured by ELISA over 1 year among 136 health care workers infected during the first COVID-19 wave and in a subgroup after booster vaccination approximately 1 year later. Furthermore, spike-protein-reactive memory T cells were quantified approximately 7 months after the infection and after booster vaccination. Thirty healthy individuals without history of COVID-19 who were routinely vaccinated served as controls. Results Levels of SARS-CoV-2-specific IgM- and IgA-antibodies showed a rapid decay over time, whereas IgG-antibody levels decreased more slowly. Among individuals with history of COVID-19, booster vaccination induced very high IgG- and to a lesser degree IgA-antibodies. Antibody levels were significantly higher after booster vaccination than after recovery from COVID-19. After vaccination with a two-dose schedule, healthy control subjects developed similar antibody levels as compared to individuals with history of COVID-19 and booster vaccination. SARS-CoV-2-specific memory T cell counts did not correlate with antibody levels. None of the study participants suffered from a reinfection. Conclusions Booster vaccination induces high antibody levels in individuals with a history of COVID-19 that exceeds by far levels observed after recovery. SARS-CoV-2-specific antibody levels of similar magnitude were achieved in healthy, COVID-19-naïve individuals after routine two-dose vaccination.

SARS-CoV-2 is a new Coronavirus, with first infections detected in humans late in 2019. The emergence of SARS-CoV-2 has led to a large outbreak in China and is currently causing outbreaks in many countries. The disease spectrum ranges from uncomplicated upper respiratory tract infections to severe viral pneumonia with multiorgan failure and death. It can be transmitted by droplets from asymptomatic or oligosymptomatic patients and possibly through aerosols in health care environments. The route of transmission and the spectrum of disease (COVID-19) has motivated many researchers to use models of influenza outbreaks or pandemics to forecast outbreaks of SARS-CoV-2 by analogy. The epicenter of China’s outbreak has been Wuhan and the Hubei province. The Chinese government has restricted travel from and to Hubei province and has implemented a number of measures to contain the outbreak. Meanwhile, the number of new cases per day in China is falling. A WHO mission has visited China and Wuhan to report on the outbreak. They corroborated the outbreak dynamic and case count reported by the Chinese government [2].

The process of Minera y Metalurgica del Boleo recovers cobalt from a complex oxide and sulfide ore by solvent extraction and electrowinning after the recovery of copper and zinc (as copper cathode and zinc sulfate monohydrate). As part of the process development, cobalt electrowinning was systematically studied with respect to temperature, pH, pitting behavior, deposit morphology, deposition stress and interfacial tension. Electrowinning test work was conducted in a bench scale diaphragm cell in a sulfate medium with control of the catholyte pH. Cobalt was deposited on a coated stainless-steel mandrel cathode with exposed circles to allow plating of disk shaped deposits over the surface of the cathode that could be easily stripped after 5–7 days of deposition. Limiting the area of plating prevents the detachment of the cobalt deposit from the cathode due to high deposition stress. The morphology and pitting behaviour varied for different commercial cobalt raw materials used for making cobalt sulfate solution as they contained different impurities or additives. The deposition behaviour changed after the solutions had an activation carbon treatment as some impurities (mainly organic compounds) were removed. In the temperature range from 50 to 65 °C, a higher temperature resulted in a brighter deposit with more pits and smaller lateral dendrites. The cobalt deposition current efficiency was around 98% at pH 3.0 and was not sensitive to temperature. With decreasing catholyte pH from 3.5 to 2.0, the cobalt current efficiency decreased from 99 to 88% and the growth of lateral dendrites were significantly suppressed. The formation of pits resulted from the adhesion of hydrogen bubbles on the cobalt deposit. The adhesion of hydrogen bubbles was determined by the prevailing surface and interfacial tensions. Anti-pitting agents were used to change the interfacial and surface tensions in such a way that the detachment of bubbles was facilitated, resulting in a pit-free cobalt deposit. The anti-pitting agents affected the deposit morphology and internal stress. The impact of the anti-pitting agents on the disengagement of organic and aqueous phases during cobalt solvent extraction was also investigated. The internal stress of the cobalt deposit as a function of temperature and anti-pitting agent dosage and the conductivities of the CoSO4-Na2SO4-H2SO4 system are reported.

Herr H., 38 Jahre, kommt in die Sprechstunde und klagt, er entwickle standig Abszesse an der Haut. Kaum sei einer abgeklungen, sei schon der nachste im Anmarsch. „Herr Doktor, ich glaube, ich habe einen Immunmangel — klaren Sie das doch bitte einmal ab!“

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.

The recovery of manganese metal from manganese carbonate precipitate by leaching–purification–electrowinning was studied. The manganese carbonate precipitate from Baja Mining Corp.'s El Boleo project was readily leached into acidic ammonium sulfate solution. The manganese extraction reached 99.7%. The manganese leachate was purified using ammonium sulfide to remove harmful impurities (Ni, Co, Cd, Cu and etc.). Manganese electrowinning was conducted in a diaphragm cell designed to eliminate edge effects and improve manganese deposition. The addition of polyacrylamide polymer had a significant leveling effect on manganese electrodeposition. However it increased the deposit internal stress and even resulted in cracking of manganese deposits at a high dosage. With increasing polyacrylamide polymer concentration, current density, and pH, the manganese current efficiency first increased, reached a maximum value and finally decreased. The manganese current efficiency decreased with increasing deposition time as the deposit became rougher and the real current density deviated from its ideal value. A reasonable catholyte circulation rate is important to maintain the optimum manganese electrodeposition. The presence of chloride in solution has a little effect on manganese deposition in its concentration range from 0 to 2 g/L. The diaphragm selection as an important part of the cell design was analyzed.

Electrolytic manganese metal has been used in a wide range of applications such as production of steel and aluminum alloys. However, manganese electrowinning is technically and commercially challenging due to a low current efficiency and high cell voltage. Rigorous purification and the use of additives are required for commercial manganese electrowinning. Some effective additives, such as selenium compounds, contaminate the metal and have negative environmental impacts. This literature review summarizes the background information on hydrogen evolution on manganese, manganese electrodeposition and its polarization behavior, effects of impurities, and the effects of additives such as selenium compounds, and their mechanisms in order to provide guidelines for development of cleaner and more efficient manganese electrodeposition conditions. Electrolytic manganese is conventionally produced from ammonium sulfate media in a diaphragm cell. Hydrogen evolution on manganese in Mn-free electrolyte is very slow compared to manganese deposition. However, it is catalyzed by manganese deposition. With increasing polarization, the manganese deposit structure changes from γ-Mn to α-Mn. Heavy metal impurities (e.g. Ni and Co) are co-deposited with manganese and catalyze the dissolution of manganese and then hydrogen evolution through the formation of galvanic micro-cells, resulting in a low manganese current efficiency. With increasing deposition time, the manganese deposit gradually becomes rougher and more dendritic, resulting in an increase in the rate of manganese dissolution. Smooth and compact deposition reduces the harmful effect of impurities and increases manganese current efficiency. Various additives (typically sulfite and selenite) have been used to counteract the harmful effects of impurities and improve manganese deposit quality. The addition of selenite (or selenate) and sulfite inhibits hydrogen evolution, increases the overpotential of manganese deposition in the low polarization region and decreases the overpotential of manganese deposition in the high polarization region, facilitates the crystallization of stable α-manganese, improves the leveling effects of the electrolyte, and finally increases the manganese current efficiency. The formation of insoluble selenides and sulfides with impurities eliminates or suppresses the generation of galvanic micro-cells and then contributes to an increase in the current efficiency of manganese deposition. Alternative additives should inhibit hydrogen evolution significantly, but manganese deposition to an appropriate degree, promote the formation of α-Mn, function as a leveling agent, have a minimum contamination of the manganese deposit and reducing capacity to stabilize the electrolyte.

Die Verhinderung einer Bakteriamie, die zur Ansiedlung von Bakterien an Herzklappen oder Klappenprothesen fuhren konnte, ist das Ziel einer antibiotischen Endokarditisprophylaxe. Fur welche Patienten und vor welchen Eingriffen ist sie indiziert?

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.

The family of Toll-like receptors (TLRs) plays a pivotal role in host defense against pathogens. However, overstimulation of these receptors may lead to uncontrolled general inflammation and eventually to systemic organ dysfunction or failure. With the intent to control overwhelming inflammation during gram-negative bacterial sepsis, we constructed soluble fusion proteins of the lipopolysaccharide (LPS)-receptor complex to modulate TLR signaling in multiple ways. The extracellular domain of mouse TLR4 and mouse myeloid differentiation factor 2 (MD-2) fusions (LPS-Trap) were linked to human immunoglobulin G Fc domains (LPS-Trap-Fc). In addition to the ability to bind LPS or gram-negative bacteria and to inhibit interleukin-6 secretion of monocytic cells after LPS treatment, LPS-Trap-Fc was able to opsonize fluorescentEscherichia coliparticles. This led to enhancement of phagocytosis by monocytic cells which was strictly dependent on the presence of the Fc region. Moreover, only LPS-Trap-Fc- and not LPS-Trap-coated bacteria were sensitized to complement killing. Therefore, LPS-Trap-Fc not only neutralizes LPS but also, after binding to bacteria, enhances phagocytosis and complement-mediated killing and could thus act as a multifunctional agent to fight gram-negative bacteria in vivo.

Aim: Bacterial translocation (BT) to mesenteric lymph nodes (MLN) in cirrhosis has been linked to impaired host defence. Phagocytosis by polymorphonuclear leucocytes (PMNLs) is the primary event in the killing of bacteria but has not been investigated in relation to the presence of BT. Methods: Mesenteric lymph nodes were harvested sterile and assessed for BT by culture techniques. Study groups included ascitic cirrhotic rats (LC), healthy controls (Con) as well as portal-vein-ligated (PVL) rats 2 days (acute PVL with and without norfloxacin) or 3 weeks after surgery (chronic PVL). PMNLs were isolated from systemic blood and the capacity to phagocytose opsonized Escherichia coli was evaluated by FACS analysis. Results: No BT was observed in Con and chronic PVL animals but 11/20 LC (55%) and six out of six acute PVL (100%) presented with BT. In the presence of BT, PMNL from PVL as well as LC rats showed significantly increased phagocytic activity as compared with controls. In contrast, PMNL from animals without BT, whether PVL or LC, exhibited phagocytic activity similar to those from control rats. The number of PMNLs involved in the phagocytic process was significantly increased only in portal-hypertensive rats with but not without BT as compared with controls. Norfloxacin did prevent BT in acute PVL animals, thereby correcting the increase in phagocytic capacity in PMNL. Conclusions: Cirrhosis per se is not associated with alterations of the phagocytic capacity of PMNL. The occurrence of BT, however, increases the phagocytic capacity of PMNL, being observed likewise in prehepatic portal hypertension, indicating an in vivo‘priming’ of PMNL by BT independent of cirrhosis.

Die Sepsis stellt trotz diverser Fortschritte der Therapie weiterhin eine grose medizinische Herausforderung dar. Die meisten Daten zur Sepsis stammen aus Studien zur Erforschung neuer Sepsismedikamente bzw. aus internationalen Kollektiven. Ziel dieser Arbeit war die Beschreibung unselektionierter Patienten mit schwerer Sepsis an einem deutschen Universitatsklinikum in Bezug auf Erreger, Mortalitat und Risikofaktoren. Von Mai 1999 bis Dezember 2002 wurden alle Patienten internistischer und chirurgischer Intensivstationen mit neu aufgetretener schwerer Sepsis und zumindest einem Organversagen in die prospektive Beobachtungsstudie „Unicenter Sepsis Survey Regensburg“ aufgenommen. 182 Patienten wurden eingeschlossen. Das mediane Alter der Patienten lag bei 58 Jahren, der mittlere SAPS-II-Wert bei 42 und die 14-Tage- bzw. 30-Tage-Mortalitat bei 25% bzw. 34%. 48% der Patienten entwickelten aufgrund einer internistischen Erkrankung, 33% nach chirurgischen Notfalleingriffen und 19% nach geplanten chirurgischen Eingriffen eine Sepsis. Chirurgische Notfallpatienten hatten hohere SAPS-II-Werte und eine schlechtere Prognose. 35% aller Patienten entwickelten ein akutes Nierenversagen. 85% der Patienten erhielten eine Therapie mit Vasopressoren, 90% mussten mechanisch beatmet werden. 105 Patienten (58%) hatten eine wahrscheinliche, 70 Patienten (38%) eine gesicherte fokale Infektion, bei sieben Patienten (4%) erwies sich abschliesend in der retrospektiven Analyse eine infektiose Genese als nicht wahrscheinlich. Die Charakteristika dieser unselektionierten Patienten mit schwerer Sepsis stimmen bezuglich Mortalitat, Erkankungsschwere und Erregerspektrum gut mit den Populationen neuerer Sepsisstudien uberein.

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.

The sympathetic nervous system is intensely activated during bacteremia, but its immediate influence on the bacterial tissue burden remains unclear. We demonstrate that prior ablation of the sympathetic nervous system decreases this dissemination of Pseudomonas aeruginosa or Escherichia coli through a mechanism of increased secretion of peritoneal tumor necrosis factor, improved phagocytic response of peritoneal cells, and increased influx of monocytes into the peritoneal cavity. When gram-positive Staphylococcus aureus strains were used, sympathectomy increased the bacterial tissue burden, which was caused by a reduction in corticosterone tonus, and decreased both interleukin-4 secretion from peritoneal cells and the influx of lymphocytes into the peritoneal cavity. In both models, the peritoneal wall was the critical border for systemic infection. These results show the dual role of the sympathetic nervous system in sepsis. It can be favorable or unfavorable, depending on the innate immune effector mechanisms necessary to overcome infection.

The family of Toll-like receptors (TLRs) is involved in the defense of an organism to microbial attack. TLR4-induced signaling is involved in infectious diseases, chronic inflammatory diseases and sepsis; therefore, we aimed at modulating TLR4-signaling via ligand-binding soluble receptors. Because recognition of microbial structures shows some species-specific traits, we specifically selected the mouse model for later in vivo studies. We first prepared the N-terminally Flag-tagged mouse (m) recombinant (r) soluble (s) fusion proteins mrsTLR4-IgGFc (T4Fc) and mrsMD-2 in Drosophila melanogaster Schneider 2 (S2) cells. The function of these molecules was tested by inhibition of synthesis of pro-inflammatory cytokines after stimulation of mouse macrophage RAW 264.7 cells with purified lipopolysaccharide (LPS). T4Fc alone had no inhibitory activity; however, a T4Fc/MD-2 complex blocked LPS activity. By analogy with `cytokine traps', we then prepared a designer molecule (LPS-Trap) by fusing MD-2 to the C-terminus of soluble TLR4 via a flexible linker. LPS-Trap significantly inhibited TNF production by LPS-stimulated RAW 264.7 cells. Thus, the T4Fc/MD-2 complex as well as the LPS-Trap blocked LPS activity in vitro and might thus represent a new therapeutic option in sepsis by neutralization of TLR4-activating ligands.

Die akute bakterielle Meningitis ist ein medizinischer Notfall. Sie hat trotz der Fortschritte in Diagnostik und Therapie weiterhin eine hohe Letalitat und eine hohe Rate an dauerhaften neurologischen Schadigungen. Seit der breiten Einfuhrung der Konjugatvakzine fur Haemophilus influenzae Typ B ist Streptococcus pneumoniae inzwischen der haufigste Erreger einer ambulant erworbenen bakteriellen Meningitis. Die zunehmende β-Lactam-Resistenz von Pneumokokken muss deshalb bei der Wahl einer empirischen Therapie berucksichtigt werden. Die klinische Diagnose einer akuten Meningitis bleibt schwierig, fehlende Zeichen eines Meningismus schliesen eine bakterielle Meningitis nicht aus. Bei allen Patienten mit klinischem Verdacht auf eine bakterielle Meningitis muss ohne Verzogerung eine empirische antibiotische Therapie begonnen werden. Zur Sicherung der Atiologie sollten bei allen Patienten zuvor Blutkulturen abgenommen und bei fehlenden klinischen Kontraindikationen zusatzlich eine Lumbalpunktion zur Liquordiagnostik durchgefuhrt werden. Aufgrund neuerer Evidenz wird die kraniale Computertomographie zum Ausschluss eines moglichen Hirndrucks vor einer Lumbalpunktion bei Verdacht auf eine akute Meningitis nur noch fur Patienten mit Risikofaktoren (> 60 Jahre; Immundefizienz oder Immunsuppression; neurologische Vorerkrankungen bekannt; neu aufgetretene zerebrale Krampfanfalle; pathologische Befunde in der klinisch-neurologischen Untersuchung uber einen Meningismus hinaus) empfohlen. Die empirische antibiotische Therapie sollte bei diesen Patienten jedoch schon vor der Computertomographie und Lumbalpunktion begonnen werden. Eine adjuvante antiinflammatorische Therapie mit Dexamethason reduziert Mortalitat und Komplikationen bei Patienten mit einer Pneumokokkenmeningitis; sie muss jedoch kurz vor oder mit der ersten Antibiotikagabe eingeleitet werden.

Central venous catheter (CVC)-related infections may be caused by micro-organisms introduced from the skin surface into deeper tissue at the time of CVC insertion. The optimal disinfection regimen to avoid catheter-related infections has not yet been defined. This study compares three different approaches. Prospective randomised trial. A tertiary care hospital. One hundred nineteen patients scheduled electively to receive 140 CVCs. Skin disinfection was performed with either povidone-iodine 10% (PVP-iodine), chlorhexidine 0.5%/propanol 70%, or chlorhexidine 0.5%/propanol 70% followed by PVP-iodine 10%. Prior to disinfection, a swab from the site of insertion was taken for culture. CVCs were removed if no longer needed or infection was suspected. All catheters were cultured quantitatively after removal. Bacteria could be isolated from 20.7% of the catheter tips. Bacterial growth was found in 30.8% of the catheters placed after skin disinfection with povidone-iodine, in 24.4% after disinfection with propanol/chlorhexidine and in 4.7% after disinfection with propanol/chlorhexidine followed by povidone-iodine (p=0.006). In 15 cases, the same organism was isolated from the skin swab and the catheter tip. Ten of these paired isolates showed the same pattern in a pulsed-field gel electrophoresis analysis. Skin disinfection with propanol/chlorhexidine followed by PVP-iodine was superior in the prevention of microbial CVC colonisation compared to either of the regimens alone. These results support the concept that catheter infections can originate from bacterial translocation at the time of catheter insertion.

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.

Das kurzliche Auftreten des schweren akuten respiratorischen Syndroms (SARS) ist das wichtigste Ereignis in der Epidemiologie infektioser Erkrankungen. Es wird durch ein neu entdecktes und vermutlich beim Menschen neu aufgetretenes Coronavirus verursacht. Durch internationale Kooperation und schnelle Reaktion konnte der Erreger rasch identifiziert und charakterisiert werden, die Epidemie lies sich erfolgreich eindammen. Die hohe Komplikationsrate und die haufige nosokomiale Ubertragung dieses Erregers haben in den Zentren der Epidemie viele Probleme verursacht. Die HIV-Infektion ist global weiter auf dem Vormarsch, nach Afrika und Sudostasien sind nun auch die Lander Osteuropas und Zentralasien von dieser Pandemie bedroht. Praventivmasnahmen und die Einfuhrung der modernen antiretroviralen Therapie machen in Landern mit hoher Pravalenz und Inzidenz Fortschritte, bisher nur mit geringen Auswirkungen auf epidemiologische Trends. Die Masnahmen der WHO und anderer internationaler Organisationen zur Eindammung oder gar Elimination wichtiger Infektionskrankheiten schreiten nur muhsam voran und haben mit vielen Schwierigkeiten zu kampfen. Ein Einsatz von Infektionserregern in militarischen Auseinandersetzungen oder auch bei terroristischen Anschlagen ist in den letzten Jahren vermehrt diskutiert und gefurchtet worden; Anstrengungen richten sich hier vor allem auf die rasche Erkennung und Pravention solcher Anschlage. Die Befurchtungen einer rasch steigenden Zahl von Patienten mit der neuen Variante der Creutzfeldt-Jakob-Erkrankung haben sich glucklicherweise bisher nicht bestatigt.

During the past 3 years new insights have been gained into the fundamental elements that underlie the pathogenesis of sepsis, and after years of frustrating failures, progress in the basic understanding of sepsis has translated into successful new therapies. These new treatment strategies have significantly improved the outcome of patients experiencing the puzzling syndrome of severe sepsis. More effective supportive therapies with early, goal-oriented therapy including volume resuscitation, catecholamine therapy and transfusion improve the chances for survival in septic shock. Novel endocrine management with hydrocortisone replacement therapy for relative adrenal insufficiency in septic shock patients and strict blood glucose control provide a survival advantage in critically ill patients. Administering appropriate antimicrobial therapy, nutritional support and ventilation protocols with low tidal volumes have now been shown to benefit septic patients. Finally, human recombinant activated protein C (drotrecogin alfa), which ameliorates sepsis-induced disseminated intravascular coagulation and exerts several other favourable effects on endothelial cells, has been shown to reduce mortality in patients with severe sepsis. On the basis of newly discovered pathophysiological mechanisms of sepsis, several other adjuvant therapies for sepsis are in various stages of preclinical and clinical development. Individualised and optimal supportive care with efforts to reverse the precipitating cause of sepsis remains the mainstay of therapy for severe sepsis. How these new and often expensive regimens will fit into the standard treatment approach to sepsis remains to be defined by future clinical investigations.

Hintergrund: Das Hyper-IgE-Syndrom (Hiob-Syndrom) ist ein seltener primarer Immundefekt, der mit rezidivierenden Staphylokokkeninfektionen und erhohten IgE-Serumspiegeln assoziiert ist.

In den vergangenen ca. drei Jahren sind im Verstandnis der Pathophysiologie und in der Therapie der Sepsis erhebliche Fortschritte erzielt worden. Nach Jahren der Frustration und Stagnation in diesem Gebiet konnen aus den jungst veroffentlichten Studien nun fur den Kliniker bessere Leitlinien zur Behandlung der Patienten mit diesem schweren Krankheitsbild abgeleitet werden. Diese Fortschritte betreffen den Bereich der supportiven Therapie mit differenzierter und vor allem rascher Volumensubstitution und Transfusion, die Endokrinologie mit Substitution des Stresshormones Cortisol durch Hydrocortison und strenge Blutzucker-Einstellung, die optimierte kalkulierte Antibiotika-Therapie und die protektive Beatmung. Schlieslich wurde durch die Modulation der disseminierten intravasalen Gerinnung und anderer physiologischer Imbalancen bei der Sepsis durch die Behandlung mit aktiviertem Protein C erstmals ein Erfolg mit einer adjuvanten Sepsis-Therapie erzielt. Rekombinantes humanes aktiviertes Protein C ist seit Ende 2001 in den USA und seit Ende 2002 auch in Europa fur die Behandlung der schweren Sepsis zusatzlich zur Standardtherapie zugelassen. Eine Reihe von weiteren Substanzen und Verfahren zur adjuvanten Sepsis-Therapie, die unterschiedliche, pathophysiologisch begrundete Ansatze verfolgen, sind in unterschiedlichen Phasen der vorklinischen und klinischen Entwicklung. Um heutzutage einen Patienten mit schwerer Sepsis optimal zu behandeln, sollte sichergestellt sein, dass dessen konventionelle und supportive Therapie nach aktuellen Gesichtspunkten optimiert wurde und individuell uberpruft werden, ob dieser Patient ein Kandidat fur eine adjuvante Sepsis-Therapie ist.

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

To review the preclinical and clinical evidence that antiendotoxin therapeutic strategies are potentially useful in the prevention and treatment of septic shock.A critical review of the literature over the past 30 yrs relating basic and clinical research on the therapeutic value of endotoxin as a target for the prevention and treatment of severe sepsis and septic shock.Bacterial endotoxin is a potent and predominant microbial mediator that induces an intense inflammatory and procoagulant response by elements of the innate immune response. This macromolecule is capable of inducing lethal septic shock in experimental animals, and a large number of preclinical studies consistently demonstrate the survival advantage of endotoxin inhibition in experimental models of sepsis. Clinical studies indicate that endotoxin may be found in the systemic circulation in the majority of humans with septic shock. Endotoxemia is largely independent of the nature of the infecting microorganism despite the fact that this molecule is specifically found in the outer membrane of Gram-negative bacteria only. Antiendotoxin strategies studied thus far have not provided reproducible survival benefits in clinical trials in septic patients.Despite compelling evidence of the critical importance of endotoxin in the pathogenesis of Gram-negative bacterial sepsis in preclinical investigations and numerous clinical interventional trials, the utility of antiendotoxin approaches to significantly reduce the mortality rate in human septic shock remains unproven. Ongoing clinical trials with specific endotoxin inhibitors should determine the potential value of this therapeutic approach to the management of septic shock.

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.

Hintergrund: Assoziiert mit Kollagenosen findet sich gelegentlich ein Antiphospholipid-Antikorper-Syndrom, charakterisiert durch thromboembolische Gefasverschlusse im arteriellen oder venosen Gefassystem. Fallbeschreibung: Bei der Patientin manifestierte sich im Alter von 13 Jahren eine Mischkollagenose (Sharp-Syndrom) mit Arthritis und Myositis. Trotz immunsuppressiver Therapie traten wiederholt Schube auf. Mit 15 Jahren entwickelte die Patientin eine Beinvenenthrombose als Ausdruck eines sekundaren Antiphospholipid-Antikorper-Syndroms. Sie wurde auf eine orale Antikoagulation eingestellt, wandte sich im Alter von 16 Jahren jedoch der “Alternativmedizin” zu und beendete sowohl die Antikoagulation als auch die immunsuppressive Therapie. Etwa 4 Wochen spater entwickelte die Patientin einen Status epilepticus, musste wegen respiratorischer Insuffizienz reanimiert werden und verstarb trotz intensivmedizinischer Therapie mit den Zeichen eines schweren Hirnodems und einer Einklemmung des Hirnstamms. Die Obduktion zeigte eine vollstandige Thrombosierung der Sinusvenen als Ursache fur das schwere Hirnodem. Schlussfolgerung: Eine Sinusvenenthrombose stellt eine seltene Manifestation eines Antiphospholipid-Antikorper-Syndroms dar. Im geschilderten Fall fiel die letale Thrombose zeitlich mit einer Phase von reaktiver Hyperkoagulabilitat nach Beendingung einer Immunsuppressiva- oder Antikoagulationsbehandlung zusammen. Dieser tratische Fall unterstreicht, dass eine dauerhafte Antikoagulation bei Patienten mit Antiphospholipid-Antikorper-Syndrom unerlasslich ist.

Die Rheumatologie wird in der Regel als eine Disziplin angesehen, in der Entscheidungen erst nach langwieriger Diagnostik und reiflicher Uberlegung gefallt werden. Aufgrund der oft geringen Dynamik der Symptome im Vergleich zu Erkrankungen wie instabile Angina pectoris oder gastrointestinale Blutungen, erscheint die Vorstellung eines rheumatologischen Patienten im Tatigkeitsfeld des Notarztes prima vista als exotischer Gedanke. Dennoch finden sich in der Rheumatologie eine Vielzahl systemischer Erkrankungen mit Krankheitsmanifestationen und Therapie-Komplikationen deren rechtzeitige Diagnosestellung fur den Organerhalt und das Leben des Patienten von entscheidender Bedeutung sein konnen. Diese Ubersicht soll daher die im klinischen Alltag wichtigsten Notfalle in der Rheumatologie beleuchten. In dieser Ubersicht wird insbesondere der aktuelle Stand zu Pathophysiologie, Diagnostik und Therapie ischamischer Komplikationen der Riesenzellarteriitis, der renalen Krise bei Sklerodermie, des katastrophalen Antiphospholipidantikorper-Syndrom, der atlantoaxialen- und atlantooccipitalen-Dislokation bei der rheumatoiden Arthritis, des Goodpasture Syndrom, der MTX-Pneumonitis, der Pneumocystis carinii Pneumonie unter Immunsuppression und der septischen Arthritis zusammengefasst (Abb.1).

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.

Background: It is routine practice to provide chemoprophylaxis for close contacts of a patient infected with meningococci. Patients and Methods: When a 17-year-old boy living in a boys' home was admitted to the hospital with septic shock caused by Neisseria meningititis, we immediately identified contact persons in the boys' home. Results: 104 contact persons were identified and screened for oropharyngeal colonization. 77 persons received chemoprophylaxis. N. meningitidis was isolated from the index case and from five of 104 throat swabs of the contact persons (three home dwellers, one staff member, one visitor). The overall carrier rate was 4.8%. All isolates showed different patterns when analyzed by pulsed-field gel electrophoresis, which was in accordance with results of serotyping by the German National Reference Center for Meningococci. Conclusion: In this non-epidemic situation, contacts between the index case, home mates, home personnel, and visitors were not close enough for effective transmission of meningococci, since no strain was found twice. This supports recommendations for the use of chemoprophylaxis in persons with intimate contact to the index patient.

□ Hintergrund Auch bei grampositiven Erregern wurden in den letzten Jahren vermehrt Antibiotikaresistenzen beobachtet. Fur die Glykopeptidantibiotika (zum Beispiel Vancomycin) ist die Resistenzsituation noch relativ gunstig. Internationale Richtlinien empfehlen, den Einsatz von Glykopeptiden auf das unbedingt notwendige Mas zu beschranken, um eine Resistenzentwicklung fur diese Substanzgruppe zu vermeiden. In Landern, in denen Antibiotikarestriktionen verbreitet Anwendung finden, uben die Klinikapotheken in der Regel diese Kontrollfunktion aus. An deutschen Krankenhausern gestaltet sich eine entsprechende Uberwachung der Antibiotikaverschreibungspraxis jedoch schwieriger, da durch die dezentrale Medikamentenbevorratung auf den Stationen die Uberprufung der Indikation einer individuellen Antibiotikaverordnung durch eine zentrale Stelle in der Regel nicht moglich ist.

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.

Vaskulitiden sind seltene, meist systemische entzundliche Erkrankungen, die das Gefassystem in unterschiedlichem Ausmas und Verteilungsmuster betreffen. Primare, atiologisch ungeklarte und sekundare, auf andere Ursachen (Infektionen, Medikamente, Tumoren) zuruckfuhrbare Formen mussen unterschieden werden. Die Panarteriitis nodosa bei der chronischen Hepatitis B und die gemischte Kryoglobulinamie bei der Hepatitis C sind klassische Beispiele fur durch Infektionen induzierte Vaskulitiden. Bei der Vielzahl an Patienten mit chronischen Virushepatitiden stellt die Entwicklung einer Vaskulitis jedoch eine seltene Komplikation dar. Auch bei der HIV-Infektion kommen Vaskilitiden vor, was durch haufige und chronische opportunistische Infektionen oder Defekte in der Immunregulation erklart werden kann. Daneben sind in Einzelberichten oder kleinen Serien eine Vielzahl von teils sehr verbreiteten Erregern als Verursacher von Vaskulitiden beschrieben worden, entweder durch direkte Infektion des Endothels oder durch die Induktion eines immunologischen Prozesses, der zur Gefasschadigung fuhrt. Es wird postuliert, das bei jenen Patienten, die durch immunologische Mechanismen ausgeloste Vaskulitiden bei Infektionen entwickeln, eine pradisponierende Reaktionsweise des Immunsystems vorliegt. Nach erfolgreicher Behandlung der Infektion bessert sich in der Regel die Vaskulitis. Da somit eine kausale Therapie moglich ist, sollte bei jeder Vaskulitis auch nach einer zugrunde liegenden Infektion gesucht werden.

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.