[Vasculitides and eosinophilic pulmonary diseases]. / Vaskulitiden und eosinophile Lungenerkrankungen.

Eosinophilic granulocytes form peripheral effector cells controlled by Th2 lymphocytes, which cause local cell, tissue, and functional disorders of infiltrated organs via the release of cytotoxic basic proteins and oxygen radicals. Diseases associated with eosinophilia include systemic and organ-related forms. The lungs are involved in eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), acute and chronic eosinophilic pneumonia, as well as in an organ manifestation in hypereosinophilic syndrome and certain parasitic diseases. In particular, the lungs are frequently affected in vasculitis of small vessels, including EGPA, granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). Among these, EGPA is the most frequent pulmonary eosinophil vasculitis representative. In addition, there are various overlap syndromes in which characteristic features of EGPA can be detected in the context of other anti-neutrophil cytoplasmic antibody (ANCA-)associated vasculitides. Occasionally, non-ANCA-associated pulmonary vasculitides occur with eosinophilia (e.g., Schönlein-Henoch purpura, Kawasaki disease, drug-induced hypersensitivity, and paraneoplastic syndrome). Herein, the pulmonary vasculitides accompanying eosinophilia are presented with respect to both the lung manifestations and pulmonary eosinophilia.

[Vasculitides and eosinophilic pulmonary diseases]. / Vaskulitiden und eosinophile Lungenerkrankungen.

Eosinophilic granulocytes form peripheral effector cells controlled by Th2 lymphocytes, which cause local cell, tissue, and functional disorders of infiltrated organs via the release of cytotoxic basic proteins and oxygen radicals. Diseases associated with eosinophilia include systemic and organ-related forms. The lungs are involved in eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), acute and chronic eosinophilic pneumonia, as well as in an organ manifestation in hypereosinophilic syndrome and certain parasitic diseases. In particular, the lungs are frequently affected in vasculitis of small vessels, including EGPA, granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). Among these, EGPA is the most frequent pulmonary eosinophil vasculitis representative. In addition, there are various overlap syndromes in which characteristic features of EGPA can be detected in the context of other anti-neutrophil cytoplasmic antibody (ANCA-)associated vasculitides. Occasionally, non-ANCA-associated pulmonary vasculitides occur with eosinophilia (e.g., Schönlein-Henoch purpura, Kawasaki disease, drug-induced hypersensitivity, and paraneoplastic syndrome). Herein, the pulmonary vasculitides accompanying eosinophilia are presented with respect to both the lung manifestations and pulmonary eosinophilia.

Lung disease and ulcerative colitis--mesalazine-induced bronchiolitis obliterans with organizing pneumonia or pulmonary manifestation of inflammatory bowel disease?

Ulcerative colitis can be associated with numerous extraintestinal organ manifestations. Pulmonary disease in inflammatory bowel disease (IBD) is supposed to be a rare entity and has to be distinguished from infectious complications and side-effects of medications used in the treatment of IBD. We present the case of a 20-year-old male patient with ulcerative colitis and a 4-week history of respiratory symptoms, malaise, fever and respiratory insufficiency under a medication with mesalazine. Computed tomography showed bilateral subpleural consolidations, bronchoscopy revealed signs of acute bronchitis. The diagnostic work-up ruled out an infectious cause. Under the tentative diagnosis of a mesalazine-induced bronchiolitis obliterans with organizing pneumonia (BOOP) the medication with mesalazine was withdrawn and the patient received a corticosteroid trial. The symptoms quickly improved and prednisone was tapered and stopped after 6 months. Unexpectedly, lung function after complete resolution of respiratory symptoms revealed a residual obstructive ventilatory defect that might be due to an asymptomatic pulmonary manifestation of ulcerative colitis. A review of the literature shows that pulmonary manifestations in IBD as well as pulmonary toxicity of mesalazine might not be as rare as expected and should be included as differential diagnoses in the work-up of respiratory symptoms in patients with IBD. A pragmatic therapeutic approach is reasonable in critically ill patients as it is not always easy to distinguish both entities.

[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.

[Bronchiolitis]. / Bronchiolitis.

Due to the variability in respect to aetiology, histopathology, lung function, imaging and clinical presentation, as well as overlapping parenchymal processes, bronchiolar disorders are generally difficult to diagnose. Thus, diseases of the small airways should generally be considered in the differential diagnostic approach to respiratory conditions. The diagnostic approach can be devided into several steps: in steps 1 (history and physical examination) and 2 (plain chest radiographs and pulmonary function tests) may point towards a bronchiolar pulmonary process. High-resolution CT (HR-CT) scanning of the chest provides three distinct HR-CT patterns (tree-in-bud sign, ill-defined centrilobular ground-glass nodules and/or pattern of mosaic attenuation, especially visible on expiratory images) which confirm a bronchiolic involvement and help to narrow down a likely diagnosis or more specific bronchiolitic diseases. In inconclusive cases, a histological diagnosis may be required. The paper presents a clinically useful algorithmic approach to diagnosis and differential diagnosis of bronchiolar disorders.

[Bronchiolitis. Part 1--anatomic features, classification, clinical presentation and imaging]. / Bronchiolitis. Teil 1--Anatomische Grundlagen, Klassifikation, klinische Präsentation und Bildgebung.

The term "bronchiolitis" refers to a broad spectrum of common conditions related to the small airways associated with a miscellaneous aetiology, histology, clinical features and course. Due to their variability, bronchiolar disorders are generally difficult to diagnose. History (smoking, collagen vascular disease, inhalational injury, medication usage, and organ transplant) may point towards a bronchiolar process. In addition, signs of systemic and pulmonary infection and evidence of air trapping may provide diagnostic hints. Although clinical presentation, physical examination, pulmonary function tests (obstructive ventilatory defect), and plain chest radiographs may demonstrate abnormalities suggesting small airways involvement, they are often non-specific and rarely diagnostic. In contrast, the high-resolution CT (HR-CT) scanning of the chest provides three distinct HR-CT patterns that assist in the diagnosis and differential diagnosis of bronchiolar conditions: (i) a tree-in-bud pattern, (ii) ill-defined centrilobular ground-glass nodules, and (iii) a mosaic attenuation pattern (best visible on expiratory images). The present paper summarises the current knowledge, the classification, imaging, and the clinical presentation of bronchiolar disorders.

[Therapy for small airways disease: basic principles and therapeutic implications]. / Therapie der kleinen Atemwege: Grundlagen und Möglichkeiten.

This paper describes the possibility of targeting the small airways. In addition to aiding in the therapy for chronic obstructive lung diseases this may prove to be invaluable in the development of treatment strategies for diseases of the bronchioli. Essential factors in peripheral lung deposition include extra-fine particles, a slow and controlled inspiratory flow and an endexspiratory breathhold of 5 - 10 sec (especially for steroids). Due to methodological difficulties, clinical data comparing steroids with larger or extra-fine particles are limited in the field of asthma therapy. However, research suggests a trend for reduced symptoms, positively affected biomarkers and decreased lung hyperinflation when steroids with extra-fine particles are used.

[Lung function diagnostics for the small airways]. / Lungenfunktionsdiagnostik der kleinen Atemwege.

In the recent years growing interest has focused on the involvement of the distal airways (internal diameter < 2 mm) in obstructive lung diseases and other pulmonary conditions. Inflammation in the small airways seems to play a major role in severe and uncontrolled asthma as a major determinant of airflow obstruction. Thus, small airways represent an important target for inhalation therapy. Currently there is no accepted single lung function parameter to detect small airway dysfunction. Various invasive and non-invasive techniques have been described. In future, non-invasive lung function testing will gain more importance. Using spirometry or body plethysmography, lung function parameters such as the ratio of forced vital capacity to slow vital capacity (FVC/SVC) and the residual volume (RV) can provide information about air trapping in small airway disease. Recent data show that techniques such as impulse oscillometry, nitrogen washout testing and analysis of exhaled nitric oxide are promising tools to assess involvement of the small airways. Impulse oscillometry is a sensitive method to calculate peripheral airway resistance, nitrogen washout allows one to detect air trapping and inhomogeneous ventilation in the distal lung, and the alveolar nitric oxide concentration represents a marker of peripheral inflammation. Further studies are needed to validate these functional tests or their combination for diagnosis and assessment of treatment response in pulmonary diseases involving small airways.

[Airway complications following lung transplantation - clinic, diagnosis, and interventional management]. / Atemwegskomplikationen nach Lungentransplantation - Klinik, Diagnose und interventionelle Behandlung.

Tracheobronchial complications following lung transplantation are defined as local structural or infectious alterations of the airways, which occur early or several months after lung transplantation (LTx). They preferentially develop in the region of the bronchial anastomosis. The most frequently reported complications are bronchial stenosis, bronchial dehiscence, exophytic excessive granulation tissue formation, tracheo-bronchomalacia, bronchial fistulas, and endobronchial infections. Airway complications are mainly attributed to ischaemia of the donor bronchus during the immediate post-transplant period. The most relevant risk factors for the development of airway complications include local infections, surgical techniques, and the immunosuppressive regimen. Thus, management of post-transplant bronchial complications requires early interventional bronchoscopic procedures including balloon bronchoplasty, cryotherapy, laser photoresection, endobronchial brachytherapy, and bronchial stents. In addition, antibiotic treatment, or non-invasive positive-pressure ventilation may be necessary. The procedures required depend on the time of occurrence, the type, and clinical relevance of the airway complication. This review summarises clinical presentation, risk factors, the diagnostic methods as well as management options for the most common LTx-associated airway complications.

[Interferon-alpha as treatment option in severe persistent uncontrolled bronchial asthma: an open label study]. / Interferon-alpha als Therapieoption bei der Behandlung des schwergradig persistierenden, unkontrollierten Asthma bronchiale: Eine offene Studie.

BACKGROUND: The purpose of this study was to evaluate the long-term safety and therapeutic effects of IFN-alpha in patients with severe persistent uncontrolled asthma on long-term oral glucocorticoid (GC) treatment. PATIENTS AND METHODS: The study included 16 patients (2 male, 14 female; age 39 years [range: 24 - 63]) with severe persistent asthma. Diagnosis and severity classification of asthma were established according to the guidelines of the "Deutsche Atemwegsliga". Eight patients stopped the therapy within 7 months due to side effects (n = 3), costs not covered by health insurance (n = 2), non-compliance (n = 2), and change of residence (n = 1). 8 patients (8 female, age 49 years [range: 35 - 68], duration of disease 16 years [range: 5 - 24]) were treated for at least 12 months with IFN-alpha (9 microg) 3 times/week. All patients were on oral glucocorticoids (GCs) for more than 5 years (average dose 17.5 [range: 5.0 - 64.0] mg/d). Clinical signs, lung function, need for reliever medication, number of emergency visits and hospitalisations and diary were assessed prior to and after 12 months of treatment. Data are given as percent of normal or median [range]. RESULTS: IFN-alpha improved lung function after 12 months: FEV1 64 vs. 75 %; FEV1/IVC 76 vs. 89 %; RV 153 % vs. 129 %; Rtot 193 vs. 111 % and morning PEF by 50 - 190 L/min. IFN-alpha also significantly reduced the use of reliever medication (10 [2 - 20] vs. 1 [0 - 3] puffs/d), nocturnal awakening (11 [4 - 30] vs. 1 [0 - 5]/month), emergency visits (7 [2 - 15] vs. 0 [0 - 5]/month) and hospitalisations (4 [1 - 8] vs. 0 [0 - 5]/year). In 5 patients the asthma attacks and nightly disturbances disappeared completely. The improvements were achieved despite a tapering of the oral GCs in all patients from 17.5 (5.0 - 64.0) to 2 (0 - 16) mg/d. In 5 patients GC treatment could be discontinued. The number of blood eosinophils decreased from 0.46 to 0.28 Gpt/L. Adverse events were transient and usually decreased within 3 to 4 weeks. Two patients developed an autoimmune thyreoiditis. CONCLUSION: In severe persistent, uncontrolled, and GC-dependent asthma, treatment with IFN-alpha leads to sustained clinical improvement and allows the reduction or discontinuation of oral GCs. Severe side effects may occur in isolated cases.

[Global Initiative for Asthma Management and Prevention--GINA 2006]. / Krankheitskontrolle als Therapieprinzip beim Asthma bronchiale.

GINA together with many other national guidelines for the clinical management of asthma recommend a disease severity assessment in order to determine the quantity and frequency of medication. This classification scheme groups patients into one of four categories (intermittent, mild-persistent, moderate-persistent, and severe-persistent). However, it is important to recognise that asthma severity includes both severity of the underlying disease and responsiveness to treatment. In addition, severity is not an unvarying feature in any individual asthma patient and disease severity may change over months or years. Thus, for ongoing asthma management, classification using the level of control may be more relevant and useful in clinical practice. The new version of the GINA guidelines 2006 recognises these limitations of severity assessment and classifies the condition according to the level of control as "controlled", "partly controlled", and "uncontrolled" asthma on the basis of daytime symptoms, restrictions of physical activity, nocturnal symptoms/awakening, need for reliever/rescue medication, lung function (PEF or FEV1) and the frequency of exacerbations. In addition, the patient is assigned to one of five treatment "steps". Each step represents treatment options that are alternatives for controlling asthma. Moreover, steps 1 to 5 provide options of increasing efficacy. In order to maintain asthma control regular monitoring and adjustment is essential. In cases where asthma is not or only partially controlled with the current treatment regimen, step-up treatment is recommended whereas disease control allows a gradual stepping-down to the lowest possible dose of medication necessary to maintain control. This novel asthma management approach based on disease control, may facilitate acceptance and use of asthma guidelines in clinical practice.

Characterization of platelet-activating factor-induced elevation of cytosolic free calcium concentration in eosinophils.

In order to evaluate the role of calcium in the activation processes in eosinophils induced by platelet-activating factor (PAF), we investigated the changes in free cytoplasmatic Ca2+ concentration using fura-2. PAF causes a rapid and transitory rise of the intracellular free calcium ion concentration [( Ca2+]i) in purified guinea pig eosinophils of approx. 1000 nM above a basal level of 120.7 +/- 36.5 nM (n = 10). The effect was dose-related with a maximum rise at 1000 nM PAF and an EC50 of 17.4 nM and specifically inhibited by the PAF antagonist WEB 2086 with an IC50 of 95.5 nM. WEB 2086 did not affect either the leukotriene B4- or the fMet-Leu-Phe-induced elevation of [Ca2+]i. The response to PAF was dependent on external Ca2+ as it was significantly inhibited by EGTA (85.6 +/- 5.4%) and Ni2+ (95.8 +/- 2.1%) but not by the dihydropyridine antagonist nimodipine. We conclude that Ca2+ entry via receptor-operated Ca2+ channels may be involved in PAF-induced degranulation of eosinophils.

Sonography of lung and pleura in pulmonary embolism: sonomorphologic characterization and comparison with spiral CT scanning.

STUDY OBJECTIVES: Despite the widespread use of lung scanning and angiography, pulmonary embolisms (PEs) remain undiagnosed in the majority of patients, suggesting the need for alternative diagnostic approaches. The present study investigates the clinical utility of transthoracic sonography (TS) for the diagnosis of PE and compares the data obtained with the technique to those obtained by spiral CT (sCT) scanning. DESIGN: This prospective study was performed using 69 patients with suspected PEs. TS was performed in all patients. In addition, sCT scanning was carried out in 62 patients. Other diagnostic procedures included the estimation of d-dimers, echocardiography, venous duplex sonography of the legs, pulmonary angiography, and ventilation/perfusion scanning. The diagnosis of PE was accepted when there was a conclusive result of these investigations or when an embolus could be visualized on a CT scan. SETTING: The Department of Pneumology in Friedrich-Schiller-University Hospital (Jena, Germany). PATIENTS: Sixty-nine patients (27 women and 42 men) with suspected PEs. RESULTS: A diagnosis of PE was established in 44 patients. Ninety-one peripheral parenchymal lesions (mean, 2.6 lesions per patient; range 1 to 9 lesions per patient) that are associated with PE were detected by TS in 35 patients (80%). Multiple, triangular, hypoechoic, and pleural-based parenchymal lesions with a localized and/or basal effusion were typical of the PEs as shown by TS. In nine patients with central PEs that had been diagnosed by CT scanning, no peripheral lesions could be detected by sonography. One patient with sonographic signs of PEs had a diffuse bronchogenic adenocarcinoma that was diagnosed at autopsy. In another patient with parenchymal lesions, pneumonia was diagnosed by CT scanning. The sensitivity of TS for detecting PEs was 80% (sensitivity of CT scanning, 82%), and the specificity of TS for detecting pulmonary lesions was 92% (specificity of CT scanning, 100%). The positive and negative predictive values of TS for the detection of PEs were 95% and 72%, respectively (positive predictive value for CT scanning, 100%; negative predictive value for CT scanning, 77%). The accuracy of TS was 84% (accuracy of CT scanning, 89%). CONCLUSIONS: TS is a noninvasive technique that is used for diagnosing parenchymal alterations, and it may serve as an additional method in the strategy for diagnosing PE.

Leukocyte infiltration and secretion of cytokines in pleural drainage fluid after thoracic surgery: impaired cytokine response in malignancy and postoperative complications.

STUDY OBJECTIVE: To assess the postoperative course of pleural leukocyte counts and cytokine concentrations in patients with malignant and nonmalignant lung disease who underwent thoracic surgery. PATIENTS AND INTERVENTIONS: A total of 21 patients undergoing thoracic surgery were included in the study. Twelve patients had a malignant disease, and 9 had a nonmalignant disease. Six patients underwent video-assisted thoracoscopy and 15 underwent thoracotomy. Pleural drainage fluid from the chest tubes was collected postoperatively at Oh, 3h, 6h, 12h, 24h, 48h, 72h, and 96 h. The same schedule, as well as one additional preoperative sample, was applied for blood collections. RESULTS: A trend toward lower concentrations of tumor necrosis factor-alpha (TNF-alpha), granulocytemacrophage colony-stimulating factor, and interleukin-10 was observed in patients with malignant disease compared to those without malignancy. These differences achieved significance for TNF-alpha in the drainage fluid of those patients with nonmalignant disease who had undergone formal thoracotomy. Patients with malignant disease showed significantly lower macrophage fractions in drainage fluid and lymphocyte fractions in serum. All patients with complications had malignant disease and showed the lowest cytokine concentrations, as well as the lowest fractions of both macrophages in drainage fluid and lymphocytes in serum. CONCLUSION: The data suggest that malignancy may lead to impairment of the wound-healing process via modification of the inflammatory cell infiltrate and locally released cytokines.

Bilateral symmetrical upper-lobe opacities: an unusual presentation of bronchiolitis obliterans organizing pneumonia.

A 45-year-old man was admitted with nonresolving fever, cough, and dyspnea 2 months after a common cold. His chest radiograph demonstrated bilateral symmetrical upper-lobe opacities reminiscent of tuberculosis. Transbronchial biopsy revealed inflammatory nonspecific alveolar lesions suggestive of bronchiolitis obliterans organizing pneumonia, which responded well clinically and radiologically to oral corticosteroids. Here, the case of a previously unreported radiographic manifestation of bronchiolitis obliterans organizing pneumonia is presented.

The pathophysiological role and therapeutic implications of platelet activating factor in diseases of aging.

Platelet activating factor (PAF) is a unique phosphoglyceride which possesses many potent biological activities relevant for the pathogenesis of diseases of the elderly. PAF is generated and released by numerous cell types and tissues and is rapidly metabolised through a well defined metabolic cycle. Its biological actions are mediated via direct and indirect stimulatory effects on target cells and tissues. The current knowledge of PAF and its role in cardiovascular disease, thromboembolism, cerebral ischaemia and neurodegenerative disorders are discussed in detail. It is likely, that in future, a better understanding of the pathophysiological and physiological roles of PAF will provide new strategies for the treatment of human diseases of aging.

Cytokines, platelet activating factor and eosinophils in asthma.

Understanding of the pathogenesis of asthma has increased considerably during the past few years. These advances were possible through scientific progress in three areas which contribute to this complex and multifaceted disease: (a) the much clearer understanding of eosinophil function; (b) the defining of lipid mediators in tissue inflammation and bronchial obstruction; and (c) the growing knowledge about the biological action of a new class of protein hormones, collectively called cytokines. In line with this, evidence has accumulated of how these components may interact with each other in providing the basis of inflammatory processes in asthma. Hence it seems appropriate to review the potential implications of this new information for the pathogenesis and therapy of this disease.

[Asthmatic airway inflammation]. / Die asthmatische Entzündung.

Asthma is an inflammatory disease of the airways even in its clinically mildest manifestation. The pathogenesis is based on complex interactions between inflammatory cells, soluble signal molecules (mediators) and structural cells as well as extracellular components of the airways. Bronchial inflammation is closely associated with bronchial hyperreactivity, airways obstruction and asthmatic symptoms. Airways inflammation causes airflow limitation via (1) acute muscular bronchoconstriction, (2) formation of mucous plugs, (3) thickening of the airway wall, and (4) fibrotic remodelling of the airways ("Remodelling"). The insights into bronchial inflammation as the basis of asthma is of principle significance for the diagnosis, prevention, and treatment of the condition.

[Asthma therapy for adults]. / Therapie des Asthma bronchiale im Erwachsenenalter.

The goal of asthma management is to achieve control of the condition. This essentially requires environmental control measures (allergen avoidance) and patient training and education. Drug treatment comprises anti-inflammatory (corticosteroids), and bronchodilatory controller therapy (long-acting beta 2-sympathomimetics, leukotriene receptor antagonists, retarded theophylline) as well as bronchodilatory medication as required (short-acting beta 2-sympathomimetics). The number and frequency of pharmacologic therapy relates to the severity of the clinical presentation. The combination of certain controller drugs (corticosteroids with long-acting beta 2-agonists, corticosteroids with leukotriene receptor antagonists, and beta 2-agonists with leukotriene receptor antagonists) yields a synergistic therapeutic effect as well as a compliance advantage.

[Recommendations for systematization of national guidelines for treatment of bronchial asthma in adulthood in Germany]. / Vorschläge zur Systematisierung der nationalen Richtlinien für die Behandlung des Asthma bronchiale im Erwachsenenalter in Deutschland.

BACKGROUND: Medical guidelines provide boundaries that are established for the medical community, within which clinical practice is considered to be acceptable. The main purpose for such guidelines is to improve the quality of care for patients. This can only be accomplished, however, if these documents are accepted and used effectively. In turn, acceptance of therapy guidelines essentially depends on both the structure and the presentation of the contents. GUIDELINES FOR THE TREATMENT OF ASTHMA were first issued in 1994 by the Deutsche Atemwegsliga. Since then, almost 4 years have passed, and our knowledge of the pathogenesis of asthma and drug efficacy has improved significantly. In addition, new classes of antiasthmatic drugs will be soon available. These developments make it necessary to adapt the guidelines to current knowledge. PROPOSALS FOR IMPROVEMENT: The paper proposes several aspects on improving the present guidelines and aims at fueling future discussions.