Macrophage activation syndrome triggered by active systemic lupus erythematosus : Successful treatment by interleukin-1 inhibition (anakinra).

This article presents a case of fulminant macrophage activation syndrome (MAS) as a rare complication of active systemic lupus erythematosus in a 33-year-old female patient. Initial presentation showed severe lupus disease exacerbation with renal involvement, hemolytic anemia, and neuropsychiatric changes. Early therapy focused on broad immunosuppression (high-dose corticosteroids and cyclophosphamide); however, disease remission could not be achieved. After an additional inflammatory focus and underlying malignancy were excluded, the triplet of pancytopenia, fever, and high ferritin levels indicated MAS, a bone marrow biopsy confirmed secondary hemophagocytic histiocytosis. Treatment with an interleukin­1 antagonist (anakinra) induced a fast, effective therapeutic success.

Diagnostic Gain from Surgical Biopsy for Interstitial Lung Disease - When is it Worth the Risk?

BACKGROUND: History, clinical presentation, lung function testing, radiographs including HRCT and nonsurgical biopsy techniques in most cases provide sufficient information for classification of interstitial lung disease (ILD). However, in a small percentage it is not possible to establish the diagnosis so that lung biopsy may be required. We analyzed under which circumstances a reduction of invasive procedures is reasonable. METHODS: Between January 1997 and December 2009 we examined 3399 specimens from 1299 patients with benign inflammatory and granulomatous diseases in whom ILD was clinically hypothesized. We compared the probability of disease according to Bayes before and after surgery which corresponds to the clinical diagnosis (a priori probability) and the final diagnosis (a posteriori probability). Additionally, procedures, operation related complications and the patients' smoking habits were documented. RESULTS: In 111 patients (8.5 %) surgical evaluation was performed (14 mediastinoscopies, 97 thoracotomies/VATS biopsies). All mediastinoscopies substantiated a epitheloid cell granulomatosis. In 30 % of all VATS procedures a prolonged air leak of more than 4 days was observed. One patient died and one had to get a new chest tube after removal. Changes of a priori/a posteriori probabilities was shown for non-smokers in Wegner's granulomatosis (0.6 vs. 2.2 %) and IPF (16.7 vs. 34.8 %), for smokers in Langerhans' cell histiocytosis (1.4 vs. 7.8 %) and IPF (16.7 vs. 33.3 %). In the majority of cases even a reduction of probability was seen. CONCLUSION: Considering complications and limited diagnostic gain, lung biopsies for diagnosis of ILD should be recommended only in selected patients.

[German guideline for diagnosis and management of idiopathic pulmonary fibrosis]. / S2K-Leitlinie zur Diagnostik und Therapie der idiopathischen Lungenfibrose.

Idiopathic pulmonary fibrosis is a fatal lung disease with a variable and unpredictable natural history and limited treatment options. Since publication of the ATS-ERS statement on IPF in the year 2000 diagnostic standards have improved and a considerable number of randomized controlled treatment trials have been published necessitating a revision. In the years 2006 - 2010 an international panel of IPF experts produced an evidence-based guideline on diagnosis and treatment of IPF, which was published in 2011. In order to implement this evidence-based guideline into the German Health System a group of German IPF experts translated and commented the international guideline, also including new publications in the field. A consensus conference was held in Bochum on December 3rd 2011 under the protectorate of the "Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP)" and supervised by the "Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften" (AWMF). Most recommendations of the international guideline were found to be appropriate for the german situation. Based on recent clinical studies "weak negative" treatment recommendations for pirfenidone and anticoagulation were changed into "weak positive" for pirfenidone and "strong negative" for anticoagulation. Based on negative results from the PANTHER-trial the recommendation for the combination therapy of prednisone plus azathiorpine plus N-acetlycsteine was also changed into strong negative für patients with definite IPF. This document summarizes essential parts of the international IPF guideline and the comments and recommendations of the German IPF consensus conference.

Usefulness of exhaled nitric oxide to guide risk stratification for bronchiolitis obliterans syndrome after lung transplantation.

The aim of this study was to assess fractional exhaled nitric oxide (FeNO) for the early diagnosis of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX). 611 FeNO measurements in 166 consecutive patients were classified depending on BOS stage at the time of assessment and course during minimum follow-up of 3 months: (1) stable non-BOS, (2) unstable non-BOS, (3) stable BOS and (4) unstable BOS. Unstable course was defined as new onset of BOS≥1 or progression of BOS. FeNO before unstable course was significantly increased in comparison to their stable counterparts (non-BOS: 28.9 ± 1.2 ppb, n = 40 vs. 16.4 ± 0.8 ppb, n = 131 and BOS: 32.5 ± 1.3 ppb, n = 35 vs. 15.3 ± 0.8 ppb, n = 26; p = 0.01 each). Average time from FeNO reading to onset of deterioration was 117 ± 9 days in non-BOS and 136 ± 9 days in BOS patients. The positive and negative predictive value of FeNO >20 ppb for BOS was 69.0% and 96.9%, respectively. Serial measurements demonstrated significantly lower mean individual variation in stable recipients as compared to stable patients switching to unstable course (3.2 ± 0.3 ppb vs. 12.7 ± 1.4 ppb, p = 0.02). In particular, the excellent negative predictive value of persistently low FeNO readings for future BOS make FeNO assessments a useful tool for continuous risk stratification after LTX.

[Non-specific interstitial pneumonia (NSIP)]. / Nicht spezifische interstitielle Pneumonie.

Non-specific interstitial pneumonia (NSIP) belongs to the group of idiopathic interstitial pneumonias (IIP). However, NSIP can also be found in several other diseases. For example, the NSIP pattern is most commonly found in interstitial lung disease due to connective tissue disease. In this review, the definition and classification, aetiology, pathogenesis and histology, clinical symptoms, serological markers, lung function parameters, radiographic signs, treatment, and prognosis of NSIP are presented. Idiopathic NSIP as a distinct form of NSIP will be discussed separately.

[Histomorphology of interstitial lung disease and pulmonary vasculitis]. / Histomorphologie interstitieller Lungengerüstveränderungen und pulmonaler Vaskulitiden.

Rheumatic diseases or collagen vascular diseases represent a heterogeneous group of immunologically mediated inflammatory disorders. The respiratory system is often affected,the causes being manifold: infection, medication toxicity and specific manifestations of immunological processes due to the underlying disease. The lung can be involved in all its components. Due to their extremely broad differential diagnosis, pulmonary vasculitic syndromes still constitute a major challenge for the pathologist. Pulmonary involvement is frequent in primary systemic vasculitis (PSV) associated with anti-neutrophil-cytoplasmic antibodies (ANCA); other PSV only rarely affect the lungs. Histomorphologically, small vessel vasculitis with neutrophil alveolitis and diffuse alveolar hemorrhage, as well as extravascular intraparenchymal or peribronchial granulomas, can point to PSV. A single biopsy is often insufficient to identify all diagnostic criteria. Therefore, the selection of suitable biopsy material and correlation with clinical, serological and radiological parameters is indispensable. Almost all forms of interstitial lung disease may be present in collagen vascular disease; however, several parallel morphological types, rather than one in isolation, are frequently found.

Lung injury following thoracic aortic occlusion: comparison of sevoflurane and propofol anaesthesia.

BACKGROUND: Halogenated anaesthetics have been shown to reduce ischaemia-reperfusion injuries in various organs due to pre- and post-conditioning mechanisms. We compared volatile and total intravenous anaesthesia with regard to their effect on remote pulmonary injury after thoracic aortic occlusion and reperfusion. METHODS: Eighteen pigs were randomized after sternotomy and laparotomy (fentanyl-midazolam anaesthesia) to receive either sevoflurane or propofol in an investigator-blinded fashion. Ninety minutes of thoracic aortic occlusion was induced by a balloon catheter. During reperfusion, a goal-directed resuscitation protocol was performed. After 120 min of reperfusion, the anaesthetic regimen was changed to fentanyl-midazolam again for another 180 min. The oxygenation index and intra-pulmonary shunt fractions were calculated. After 5 h of reperfusion, a bronchoalveolar lavage was performed. The total protein content and lactate dehydrogenase activity were measured in epithelial lining fluid (ELF). Alveolar macrophage oxidative burst was analysed. The wet to dry ratio was calculated and tissue injury was graded using a semi-quantitative score. Ten animals (n=5 for each anaesthetic) without aortic occlusion served as time controls. RESULTS: The oxygenation index decreased and the intra-pulmonary shunt fraction increased significantly in both occlusion groups. There were no significant differences between sevoflurane and propofol with respect to the oxygenation index, ELF composition, morphologic lung damage, wet to dry ratio and alveolar macrophage burst activity. Differences were, however, seen in terms of systemic haemodynamic stability, where catecholamine requirements were less pronounced with sevoflurane. CONCLUSION: We conclude that the severity of remote lung injury was not different between sevoflurane and propofol anaesthesia in this porcine model of severe lower-body ischaemia and reperfusion injury.

[Pleural metastases of a typical bronchial carcinoid 7 years after lobectomy]. / Pleurales Rezidiv eines typischen pulmonalen Karzinoids 7 Jahre nach Operation.

BACKGROUND: Bronchial carcinoids are a rare differential diagnosis of solitary pulmonary nodes. Because of their typical manifestation in the major bronchi, carcinoid tumours are visible regularly via bronchoscopy where they show a typical picture. In lymph node-negative disease a favourable outcome can be expected. Typically metastases develop in the lung, liver, brain, bone and adrenal glands. CASE REPORT: Seven years after lobectomy of a bronchial carcinoid, a slow-growing thickening of the pleura parietalis was noted in a 54-year-old male patient. No clinical signs of neuroendocrine activity were seen. The histological diagnosis of pleural metastases was established via trans-thoracic punctation. Pleural metastases of bronchial carcinoids are extremely rare. Only two other cases have been reported so far. Palliative cytotoxic chemotherapy was started. CONCLUSIONS: The postoperative prognosis of bronchial carcinoids in lymph node-negative disease is excellent. Metastatic disease--as in the rare case of pleural metastases shown here--remains a therapeutic dilemma. Extensively evaluated concepts for adjuvant or palliative settings do not exist. Further research is needed.

Transgenic animals in experimental xenotransplantation models: orthotopic heart transplantation in the pig-to-baboon model.

Pig organs are at risk for hyperacute and acute vascular rejection mediated by anti-pig antibodies, mainly binding to the Galalpha(1,3)Gal epitope. Acute cellular rejection is characterized by progressive infiltration of mononuclear cells. There is an ongoing search for immunosuppressive regimens that provide adequate protection against all patterns of xenograft rejection, but have no severe impact on the condition of xenograft recipients. Herein orthotopic heart transplantations were performed from hDAF or hCD46 piglets to nonsplenectomized baboons. Basic immunosuppression consisted of tacrolimus, sirolimus, GAS914, steroids, and ATG. Group 1 received basic immunosuppression. Group 2 was additionally treated with rituximab and group 3 with half-dose cyclophosphamide. Group 4 received cyclophosphamide and an anti-HLA-DR antibody. Three baboons received GAS914 and TPC. Monitoring included the regular assessment of anti-porcine antibodies, blood counts, therapeutic drug monitoring, and graft histology. Two grafts failed due to technical mistakes. In group 1, baboons died after 1 and 9 days. In group 2, maximum survival was 30 hours. In group 3, baboons lived 20 hours, 25 days, and 14 days. Group 4 survival times were 9.5 hours, 5.5 hours, 4 days, 34 hours, and 3 days. An increase of non-Galalpha(1,3)Gal antibodies was observed. Depositions of immunoglobulins and complement revealed a humoral rejection process. No cellular infiltration could be observed. In conclusion, suppressing cellular rejection with half-dose cyclophosphamide together with tacrolimus and sirolimus produced longer graft survival with a good general condition. Prevention of acute xenograft rejection further needs inhibition of non-Galalpha(1,3)Gal cytotoxicity by sufficient depression of B-cell activation.

Outcome following lung resections for pT1 non-small cell lung cancer.

AIMS: To analyse the outcome of patients with pT1 NSCLC treated at our institution by antero-lateral thoracotomy, anatomical lung resections and mediastinal lymph node dissection between 1980 and 2001. METHODS: Follow-up data were obtained retrospectively from 1980 to 1990 and prospectively after 1990. Survival was analysed using the Kaplan-Meier method. RESULTS: Histopathological examinations revealed mediastinal lymph node infiltration in 27.6% (pN1 17.8% and pN2 9.8%). pN2 was classified in 14.1% of adenocarcinomas compared to 6.2% of squamous cell carcinomas. Median overall survival of patients with pT1 carcinomas was 89+16 months (median+standard error). Histopathological N-classification indicates differential prognostic and therapeutic implications in pT1 adeno- and squamous cell carcinomas. CONCLUSIONS: Complete lymph node dissection is required for all patients with T1 NSCLC treated by either open surgery or VATS resection. Histopathological N-classification indicates differential prognostic and therapeutic implications in pT1 adeno- and squamous cell carcinomas.

Fluorescent microspheres reveal different regional blood flow in hyperacutely rejected nontransgenic and hDAF pig hearts.

Classic features of hyperacute rejection show differential severity in the inner compared to the outer myocardium. In the present study, regional blood flow (RBF) measured by fluorescent microspheres served as a marker of the extent of hyperacute rejection. Using a working heart model, hearts of nontransgenic and hDAF transgenic pigs were perfused with human blood. Additionally, hDAF transgenic pig hearts were perfused with human blood containing GAS914 or the GPIIb/IIIa inhibitor tirofiban. Injections of fluorescent microspheres into the donor heart were performed in situ and during perfusion. Reference arterial blood samples were collected from the inferior aorta and the afterload line. Perfusion was terminated before hyperacutely rejected hearts failed to pump against the afterload column. RBF was determined in tissue samples of standardized areas of the left atrium and ventricle. Each specimen was divided into subepicardial and subendocardial tissue samples. Fluorescence intensity was measured using an automated luminescence spectrometer. At the end of perfusion with human blood, hyperacutely rejected nontransgenic pig hearts showed a higher RBF in the subendocardium. In hDAF-transgenic pig hearts perfused with unmodified human blood the subendocardial/subepicardial blood flow ratio changed in favor of the subepicardium. This ratio was not further improved by GAS914. In contrast, tirofiban was able to assimilate subepicardial and subendocardial blood flow. In conclusion, RBF of hyperacutely rejected pig hearts was inhomogeneous. Inhibition of complement activation improved the reduced subepicardial RBF, but depletion of antibodies had no positive effect. The ability of tirofiban to further increase subepicardial RBF affirms thrombosis of subepicardial veins as the defining characteristic of hyperacute rejection.

Combining the hDAF transgene with the GP IIb/IIIa inhibitor tirofiban improves heart performance and reduces myocardial damage following hyperacute rejection in an ex vivo perfusion model.

Xenograft rejection is associated with vascular injury resulting at least in part from platelet activation, and rejected xenografts invariably demonstrate intravascular thrombosis. Assuming that complement activation is a major determinant of humoral immune reactions bringing about platelet-endothelial cell interactions, we tested the effects of the specific platelet glycoprotein IIb/IIIa inhibitor tirofiban in combination with the human decay accelerating factor (hDAF) transgene on hyperacute rejection of pig hearts. Four groups were studied in a working heart-perfusion model. Pig hearts transgenic for hDAF and nontransgenic pig hearts were perfused with human blood containing tirofiban or with unmodified human blood. Cardiac output, stroke work index, and creatine phosphokinases were measured for the evaluation of the extent of myocardial damage. Consumption of complement components was determined. Endothelial deposition of fibrin and intravascular thrombosis were evaluated. Tirofiban improved cardiac output and stroke work index of nontransgenic pig hearts and was able to further increase hemodynamic function of hDAF transgenic pig hearts. Low levels of creatine phosphokinases also revealed a cardioprotective effect of tirofiban. However, a further extension of the survival of hDAF transgenic pig hearts could not be achieved, although tirofiban prolonged beating time of nontransgenic pig hearts. Tirofiban was able to reduce the consumption of complement components independently of hDAF. Intravascular evidence of fibrin and thrombosis tended to be particularly reduced by the combination of tirofiban and hDAF. Thus, the application of tirofiban together with hDAF improves the performance of pig hearts by reducing myocardial damage and intravascular thrombosis.

Influence of long-term preservation with endobronchially administered perfluorodecalin on pulmonary graft function.

BACKGROUND: Experimental studies demonstrated a suppression of oxygen-derived free radicals, reduced adhesion of activated neutrophils on the endothelium and an increase of de novo synthesis of surfactant during liquid ventilation with perflurocarbon. The purpose of this study was to assess the pulmonary graft function after preservation with endobronchially administered perfluorocarbon as an alternative to flush perfusion. METHODS: Native bred pigs underwent orthotopic left lung transplantation. Donor lungs were flushed in situ with either a low-potassium dextran solution (LPD, n=6) or a perfluorochemical was administered endobronchially (PFC, n=6) and were then stored after removal for 18 hr at 4 degrees C. Pulmonary graft function was assessed after reperfusion for 5 hr by measuring pulmonary gas exchange and hemodynamics during isolated ventilation and perfusion. Tissue specimens were taken for analysis of morphology and wet/dry ratio. All values were compared to a sham-operated group (n=6). RESULTS: Pulmonary gas exchange of the graft revealed reduced paO2 values and elevated paCO2 values in the PFC group throughout the observation period as compared with the LPD group and sham group. Endothelial alterations and fibrin exudate in the PFC group were significantly more pronounced. Lungs in the LPD group showed functional and morphological recovery close to sham group. CONCLUSIONS: Long-term preservation with endobronchially administered perfuorocarbon is possible. Impaired pulmonary graft function and pronounced morphological alterations indicate an aggravation of the ischemic reperfusion injury after lung transplantation compared to LPD preserved lungs.

Hypothermic storage alone in lung preservation for transplantation: a metabolic, light microscopic, and functional analysis after 18 hours of preservation.

BACKGROUND: Current lung preservation consists of flushing of the donor organs, with successive hypothermic storage in an inflated state. Recently, hypothermic storage alone was reported to be superior in terms of functional recovery. This study was designed to investigate the metabolic, morphologic, and functional consequences of hypothermic storage alone, in experimental lung preservation. METHODS: Orthotopic left-sided lung transplantation was performed in pigs. Donor lungs were flushed with Euro-Collins solution (n=6) or simply explanted (n=6) and stored for 18 hr at 4 degrees C. After this, left-sided single lung transplantation was performed. Sham-operated animals (n=6) served as control. Morphology and metabolism were analyzed in normal lungs, after ischemia and at the end of reperfusion. Gas exchange and pulmonary hemodynamics of the transplanted organs were measured, after exclusion of the native lung from perfusion and ventilation. RESULTS: Metabolic and morphologic evaluation did not show a significant difference between the groups at the end of ischemia. Lungs preserved by hypothermia alone showed a functional recovery close to sham-operated animals and superior to flushed organs. CONCLUSIONS: Hypothermia alone is a sufficient means of preservation for explanted lungs for at least 18 hr.

Lymphangioleiomyomatosis: recurrence after single lung transplantation.

Lymphangioleiomyomatosis (LAM) is a rare disease which afflicts young women of childbearing age. Recently, it has been listed as an indication for lung transplantation. We describe a case of recurrent LAM in a 31-year-old woman occurring in the allograft of a male donor after single lung transplantation. Nonisotopic in situ hybridization shows that the smooth muscle cell proliferation is of donor origin.

Cellular chimerism of the lung after transplantation. An interphase cytogenetic study.

The present study evaluated the origin of endothelial and epithelial cells, as well as of lymphocytes and macrophages, after lung transplantation. Biopsy specimens from patients who underwent lung and heart-lung transplantation and received organs of sex-mismatched donors were studied by means of nonisotopic in situ hybridization with DNA probes of the X and Y chromosome. By means of monoclonal antibodies against leukocytes, T and B lymphocytes, and macrophages, the various infiltrating cell types were analyzed. In all allografted lungs, the endothelial cells and bronchial and alveolar epithelium retained the donor sex type. The lymphocytes of the donor were almost completely replaced by recipient cells 1 month after transplantation. Low numbers of alveolar macrophages of the donor were present during the entire period under study. Low numbers of donor lymphocytes and high numbers of donor alveolar macrophages in the allografted lung seem to be correlated with a worse clinical course.

Pulmonary graft function after long-term preservation of non-heart-beating donor lungs.

BACKGROUND: Critical organ shortage in lung transplantation could be attenuated by the use of non-heart-beating donor (NHBD) lungs. In addition, prolonged ischemic tolerance of the organs would contribute to the alleviation of organ shortage. The aim of this study was to investigate pulmonary graft function of NHBD lungs after long-term hypothermic storage. METHODS: Twelve native-bred pigs (bodyweight 20 to 30 kg) underwent left lung allotransplantation. In the heart-beating donor (HBD) group, lungs were harvested immediately after cardiac arrest. In the NHBD group, lungs were subjected to a warm ischemic period of 90 minutes before harvesting. After a total ischemic time of 19 hours, pulmonary grafts in both groups were reperfused and pulmonary graft function was assessed. All values were compared with a sham-operated control group. RESULTS: Pulmonary graft function in the HBD group was excellent. In the NHBD group, pulmonary gas exchange was impaired, but still provided good graft function compared with the excellent graft function in the HBD group. Pulmonary vascular resistance was even lower in the NHBD group. In the NHBD group, calculated intrapulmonary shunt fraction (Qs/Qt) was significantly increased compared with the sham-group. Histologic alteration and wet-to-dry ratio did not differ significantly between the HBD and NHBD group. CONCLUSIONS: We conclude that NHBD lungs (90 minutes of warm ischemic time) have the potential to alleviate organ shortage in lung transplantation even after an extended total ischemic time.

[Penetrating aortic ulceration: an unusual form of aortic dissection]. / Die penetrierende Aortenulzeration: Eine Sonderform der Aortendissektion.

PURPOSE: The aim was to present clinical findings and imaging criteria for patients with aortic ulcers of the thoracic aorta. METHODS: From 1993 to 1996 computed tomography of patients suffering from acute thoracic pain and suspected pathologies of the aorta were reviewed for penetrating aortic ulcers. Pathoanatomical correlation was done by autopsy in three cases and with intraoperative inspection in two cases. MRI was available in three patients and angiography in 5 patients. RESULTS: 9 patients with aortic ulcers could be identified. The imaging criteria in CT were: 1. Hyperdense wall thickening on unenhanced CT scans (medial haematoma). 2. Displaced intimal calcifications outlining the lumen. 3. Small contrast-filled ulcer. 4. Absence of a contrast-filled false lumen. In 4 of the 9 cases the aorta ascendens was affected. The clinical presentation is that of an elderly patient with acute onset of thoracic pain and generalised atherosclerosis due to hypertension and nicotine abuse. DISCUSSION: Penetrating ulcers with haematoma of the media are a special case of aortic dissection, with different features on unenhanced and enhanced CT scans.