[Sarcoidosis and berylliosis]. / Sarkoidose und Berylliose.

Sarcoidosis and berylliosis (chronic beryllium disease, CBD) are granulomatous diseases and are phenocopies which cannot be differentiated based on the clinical presentation. Whereas for sarcoidosis the eliciting agent is unknown, for berylliosis an exposure to beryllium (mostly as occupational exposure) can be confirmed that therefore induces a sensitization against beryllium. The diagnosis is generally made in patients with a typical clinical presentation, the histological proof of a non-necrotizing granuloma and the exclusion of other diseases causing granulomas. In most cases, granulomas can be detected in the lungs and/or (intrathoracic) lymph nodes. The proof of sensitization to beryllium for the differential diagnosis can be performed with a so-called beryllium lymphocyte proliferation test in peripheral mononuclear blood cells or cells from a bronchoalveolar lavage. The objectives of treatment are avoidance of functional organ impairment and symptom control. Immunosuppressive therapy (initially mostly with corticosteroids) and supportive measures can prove beneficial; however, in many cases clinical observation can be sufficient because of stable disease or spontaneous resolution. In addition, further beryllium exposure must be avoided, which mostly necessitates a change of the workplace.

[Case Report with Differential Diagnostic Aspects of Sarcoidosis]. / Differenzialdiagnostische Aspekte der Sarkoidose anhand eines Fallberichts.

A 73-year-old non-atopic patient had developed at the age of 29 shortness of breath on exertion, general malaise, enlarged axillary lymph nodes and nodular cutaneous eruptions. Based on the presence of bihilar lymphadenopathy, the diagnosis of sarcoidosis was made at that time without any histological investigations and without taking detailed case history. Administration of systemic steroids resulted in remission. However, 12 years later, there was a relapse with alterations of lung parenchyma, followed by a more chronic course of the disorder. Since this relapse, an obstructive-restrictive ventilation defect requiring treatment has persisted till today. About five years ago and at the insistence of the patient, clarifying diagnostics were performed. The case shows the important role of a detailed case history including occupational history. Its failure not only led to disadvantages to the patient but also to incorrect social insurance handling and missing appropriate preventive measures with regard to co-workers.

An official American Thoracic Society statement: diagnosis and management of beryllium sensitivity and chronic beryllium disease.

RATIONALE: Beryllium continues to have a wide range of industrial applications. Exposure to beryllium can lead to sensitization (BeS) and chronic beryllium disease (CBD). OBJECTIVES: The purpose of this statement is to increase awareness and knowledge about beryllium exposure, BeS, and CBD. METHODS: Evidence was identified by a search of MEDLINE. The committee then summarized the evidence, drew conclusions, and described their approach to diagnosis and management. MAIN RESULTS: The beryllium lymphocyte proliferation test is the cornerstone of both medical surveillance and the diagnosis of BeS and CBD. A confirmed abnormal beryllium lymphocyte proliferation test without evidence of lung disease is diagnostic of BeS. BeS with evidence of a granulomatous inflammatory response in the lung is diagnostic of CBD. The determinants of progression from BeS to CBD are uncertain, but higher exposures and the presence of a genetic variant in the HLA-DP ß chain appear to increase the risk. Periodic evaluation of affected individuals can detect disease progression (from BeS to CBD, or from mild CBD to more severe CBD). Corticosteroid therapy is typically administered when a patient with CBD exhibits evidence of significant lung function abnormality or decline. CONCLUSIONS: Medical surveillance in workplaces that use beryllium-containing materials can identify individuals with BeS and at-risk groups of workers, which can help prioritize efforts to reduce inhalational and dermal exposures.

Chronic beryllium disease: computed tomographic findings.

Chronic beryllium disease is a rare multisystem granulomatous disease predominantly involving the lungs and resulting from an immunologic response to long-term occupational exposure. Computed tomography of the chest reveals important lung parenchymal and mediastinal findings and plays an important role in the diagnosis and follow-up assessment of patients with chronic beryllium disease. Its significance lies in the exact localization and evaluation of the extent of lesions. We present an overview of the subject and a pictorial review of the spectrum of computed tomographic features of beryllium disease.

Long-term complications and prognosis of chronic beryllium disease.

BACKGROUND: Chronic beryllium disease (CBD) is a rare disease, and there are no previous reports that have followed CBD patients over several decades. Thus, the long-term complications and prognosis of this illness still remain unclear. OBJECTIVE: The aim of this study was to investigate long-term complications and prognosis of CBD patients. STUDY DESIGN AND METHODS: This was a retrospective study based on the medical records of all CBD patients diagnosed at Kyoto University Hospital between the period 1973 to the present day. Ultimately, ten patients whose diagnoses had been made during the period 1973 to 1977 were included. Long-term physiological and radiological change, complications and prognosis of these patients were investigated. RESULTS: Three patients completely remitted, and one died of cor-pulmonale. Among the remaining six patients, four have been followed up for more than thirty years in our institute. The majority developed mixed patterns of lung function impairment, cavity lesions of the lung, pneumothorax, and respiratory infections. CONCLUSIONS: Long-term prognosis of CBD was poor with several complications due to chronic parenchymal and airway lesions.

Recombinant HLA-DP2 binds beryllium and tolerizes beryllium-specific pathogenic CD4+ T cells.

Chronic beryllium disease is a lung disorder caused by beryllium exposure in the workplace and is characterized by granulomatous inflammation and the accumulation of beryllium-specific, HLA-DP2-restricted CD4+ T lymphocytes in the lung that proliferate and secrete Th1-type cytokines. To characterize the interaction among HLA-DP2, beryllium, and CD4+ T cells, we constructed rHLA-DP2 and rHLA-DP4 molecules consisting of the alpha-1 and beta-1 domains of the HLA-DP molecules genetically linked into single polypeptide chains. Peptide binding to rHLA-DP2 and rHLA-DP4 was consistent with previously published peptide-binding motifs for these MHC class II molecules, with peptide binding dominated by aromatic residues in the P1 pocket. 9Be nuclear magnetic resonance spectroscopy showed that beryllium binds to the HLA-DP2-derived molecule, with no binding to the HLA-DP4 molecule that differs from DP2 by four amino acid residues. Using beryllium-specific CD4+ T cell lines derived from the lungs of chronic beryllium disease patients, beryllium presentation to those cells was independent of Ag processing because fixed APCs were capable of presenting BeSO4 and inducing T cell proliferation. Exposure of beryllium-specific CD4+ T cells to BeSO4 -pulsed, plate-bound rHLA-DP2 molecules induced IFN-gamma secretion. In addition, pretreatment of beryllium-specific CD4+ T cells with BeSO4-pulsed, plate-bound HLA-DP2 blocked proliferation and IL-2 secretion upon re-exposure to beryllium presented by APCs. Thus, the rHLA-DP2 molecules described herein provide a template for engineering variants that retain the ability to tolerize pathogenic CD4+ T cells, but do so in the absence of the beryllium Ag.

[Chronic beryllium disease: a model of interaction between environmental exposure and genetic predisposition. Pathogenesis and clinical features (Part 2)]. / Bérylliose pulmonaire chronique (2e partie). Pathogénie, expression clinique, prévention et législation.

INTRODUCTION: Chronic beryllium disease (CBD) is an occupational lung disease caused by the inhalation of beryllium dust, fumes or metallic salts. CURRENT DATA: Beryllium affects the lungs via particles deposited in the pulmonary alveoli. These are ingested by alveolar macrophages which act as antigen presenting cells to CD4+ T lymphocytes. T lymphocytes proliferate in response to beryllium antigens and combined with macrophages produce numerous epithelioid granulomas with the release of inflammatory cytokines (IFNgamma, IL-2, TNFalpha and IL6) and growth factors. Beryllium induces macrophage apoptosis which reduces its clearance from the lung which in turn contributes to the host's continual re-exposure and thus a chronic granulomatous disorder. Pulmonary granulomatous inflammation is the primary manifestation of CBD, but the disease occasionally involves other organs such as the liver, spleen, lymph nodes and bone marrow. The clinical, radiological, and histopathological features of CBD can be difficult to distinguish from sarcoidosis. The Beryllium lymphocyte proliferation test (BeLPT) demonstrates a beryllium specific immune response, confirms the diagnosis of CBD, and excludes sarcoidosis. CONCLUSIONS AND PERSPECTIVES: CBD provides a human model of pulmonary granulomatous disease produced by an occupational exposure, occurring more frequently in those with a genetic pre-disposition. It can be differentiated from sarcoidosis by specific immunological testing.

Beryllium health effects in the era of the beryllium lymphocyte proliferation test.

The beryllium lymphocyte proliferation test (BeLPT) has revolutionized our approach to the diagnosis, screening, and surveillance of beryllium health effects. Based on the development of a beryllium-specific cell-mediated immune response, the BeLPT has allowed us to define early health effects of beryllium, including beryllium sensitization (BeS), and chronic beryllium disease (CBD) at a subclinical stage. The use of this test as a screening tool has improved our understanding of these health effects. From a number of studies it is apparent that BeS precedes CBD and develops after as little as 9 weeks of beryllium exposure. CBD occurs within 3 months and up to 30 years after initial beryllium exposure. Exposure-response variables have been associated with BeS/CBD, including work as a machinist, chemical or metallurgical operator, laboratory technician, work in ceramics or beryllium metal production, and years of beryllium exposure. Recent studies have found BeS and CBD in workplaces in which the majority of exposures were below the 2 microg/m3 OSHA time-weighted average (TWA). Ideally, the BeLPT would be used in surveillance aimed at defining other risk-related processes, determining exposure variables which predict BeS and CBD, and defining the exposure level below which beryllium health effects do not occur. Unfortunately, the BeLPT can result in false negative tests and still requires an invasive procedure, a bronchoscopy, for the definitive diagnosis of CBD. Thus, research is needed to establish new tests to be used alone or in conjunction with the BeLPT to improve our ability to detect early beryllium health effects.

Chronic beryllium disease: diagnosis and management.

Chronic beryllium disease is predominantly a pulmonary granulomatosis that was originally described in 1946. Symptoms usually include dyspnea and cough. Fever, anorexia, and weight loss are common. Skin lesions are the most common extrathoracic manifestation. Granulomatous hepatitis, hypercalcemia, and kidney stones can also occur. Radiographic and physiologic abnormalities are similar to those in sarcoidosis. While traditionally the pathologic changes included granulomas and cellular interstitial changes, the hallmark of the disease today is the well-formed granuloma. Immunologic studies have demonstrated a cell-mediated response to beryllium that is due to an accumulation of CD4+ T cells at the site of disease activity. Diagnosis depends on the demonstration of pathologic changes (i.e., granuloma) and evidence that the granuloma was caused by a hypersensitivity to beryllium (i.e., positive lung proliferative response to beryllium). Using these criteria, the diagnosis of chronic beryllium disease can now be made before the onset of clinical symptoms. Whether, with early diagnosis, the natural course of this condition will be the same as when it was traditionally diagnosed is not known. Currently, corticosteroids are used to treat patients with significant symptoms or evidence of progressive disease.

Chronic beryllium disease.

Chronic beryllium disease is a multisystem granulomatous disease caused by industrial exposure to beryllium dust or fumes. It is thought to represent a hypersensitivity disorder rather than a true pneumoconiosis. The lung is the primary organ of involvement, and many of the radiographic features resemble sarcoid.

Development and clinical application of a portable oxygen concentrator.

We have produced a compact, lightweight oxygen concentrator, using a newly-developed polymer of poly [1-(trimethylsilyl)-1-propyne] with a performance, i.e. oxygen permeability, of 61 x 10 cm3 (STP) cm/cm2 s cmHg, which is 17 times higher than that of the membrane material of conventional concentrators. The oxygen and nitrogen selectivity was 1.80. The dimensions of the apparatus are 325 x 180 x 150 mm and it weighs about 4.0 kg. It is actuated by a battery (DC 12 V, 5.6 Ah), with a 100 V AC source and a car battery (12 V) source also available. The power consumption is 70 W. The generated oxygen concentration is about 30%, and the maximum flow rate is 41/min. Applying 10 samples of various chronic pulmonary diseases to the subject, the suction of oxygen from the apparatus in the patients' rest state was conducted. An increase in the PaO2, from an average of 59.1 Torr before the suction to an average of 68.5 Torr after the suction, together with easing of breathing, was indicated. The usefulness of this apparatus for supplying portable oxygen-treatment to patients with chronic respiratory disease is shown.

Hygienic and toxicological aspects of occupational and environmental exposure to beryllium.

As the production of missile, nuclear devices and electronics grew and modern industrial technologies emerged the risk of the occupational exposure to beryllium has become increasingly common and widespread. The environmental burden of beryllium is also on the increase, not only as a result of emissions from plants producing and processing beryllium, or its alloys and compounds, but also from burning coal of higher beryllium content in some localities. This article discusses primarily the hygienic and toxicologic aspects of beryllium and its threat to human health. The following topics are included in this review: occurrence, production and uses of beryllium; its metabolism and experimental toxicology; clinical toxicology and pathogenesis of berylliosis; hygienic and epidemiologic aspects of berylliosis; berylliosis treatment and prevention. Berylliosis is here characterized as a disease combining clinical manifestations of pneumosclerosis, allergy to beryllium and, in its granulomatous form, autoimmune reactions. Importantly, the available technical means and measures can ensure that the both occupational and environmental exposure to beryllium can be kept below the established MAC values. If occasionally impossible, special preventive measures should be adopted. It is essential that all persons with allergy be prophylactically excluded from work at risk of exposure to beryllium.