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AMERICAN THORACIC SOCIETYDOCUMENTS
An Ofcial American Thoracic Society Statement: Diagnosis andManagement of Beryllium Sensitivity and Chronic Beryllium DiseaseJohn R. Balmes, Jerrold L. Abraham, Raed A. Dweik, Elizabeth Fireman, Andrew P. Fontenot, Lisa A. Maier,Joachim Muller-Quernheim, Gaston Ostiguy, Lewis D. Pepper, Cesare Saltini, Christine R. Schuler, Tim K. Takaro,and Paul F. Wambach; on behalf of the ATS Ad Hoc Committee on Beryllium Sensitivity and Chronic Beryllium Disease
THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS, June 2014
Rationale: Beryllium continues to have a wide range of industrialapplications. Exposure to beryllium can lead to sensitization (BeS)and chronic beryllium disease (CBD).
Objectives: The purpose of this statement is to increase awarenessand knowledge about beryllium exposure, BeS, and CBD.
Methods: Evidence was identied by a search of MEDLINE. Thecommittee then summarized the evidence, drew conclusions, anddescribed their approach to diagnosis and management.
Main Results: The beryllium lymphocyte proliferation test is thecornerstone of bothmedical surveillance and the diagnosis of BeS andCBD.A conrmed abnormal beryllium lymphocyte proliferation testwithout evidence of lung disease is diagnostic of BeS. BeS with
evidence of a granulomatous inammatory response in the lung isdiagnostic of CBD. The determinants of progression from BeS toCBDareuncertain, but higher exposures and the presence of a geneticvariant in the HLA-DP b chain appear to increase the risk. Periodicevaluation 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 withCBD exhibits evidence of signicant lung function abnormality ordecline.
Conclusions:Medical surveillance in workplaces that useberyllium-containingmaterials can identify individuals with BeS andat-risk groups of workers, which can help prioritize efforts to reduceinhalational and dermal exposures.
ContentsOverviewIntroductionMethodsEpidemiologyGenetic SusceptibilityImmunopathogenesisPathologyDiagnostic Criteria
BeLPTDiagnostic Criteria for BeSDiagnostic Criteria for CBD
EvaluationClinical Manifestations of BeSand CBD
Diagnostic Evaluation for BeSand CBD
Natural History andManagement
Natural History andManagementof BeS
Natural History andManagementof CBD
Many workers are exposed to berylliumthroughout the world, and sensitization tothe metal continues to occur. To address thisproblem, an international committee ofexperts was convened to write a statementabout beryllium sensitization (BeS) andchronic beryllium disease (CBD). Afterthoroughly reviewing the literature, thecommittee summarized the relevant evidence,
drew conclusions, and described their usualapproach to diagnosis and management.
d The beryllium lymphocyte proliferationtest (BeLPT) is used for medicalsurveillance and the diagnosis of BeS andCBD. A BeLPT is considered abnormalif two or more of the six stimulationindices exceed the normal range. A test istypically considered borderline if onlyone of the six stimulation indices exceedsthe normal range.
d A diagnosis of BeS in beryllium-exposedworkers undergoing medical surveillancecan be based on two abnormal bloodBeLPTs, one abnormal and oneborderline blood BeLPT, or oneabnormal bronchoalveolar lavage (BAL)BeLPT. Workers identied as having BeSare evaluated for CBD.
An Executive Summary of this document is available at http://www.atsjournals.org/doi/suppl/10.1164/rccm.201409-1722ST/suppl_file/Executive_Summary.pdf
Am J Respir Crit Care Med Vol 190, Iss 10, pp e34e59, Nov 15, 2014
Copyright 2014 by the American Thoracic SocietyDOI: 10.1164/rccm.201409-1722ST
Internet address: www.atsjournals.org
e34 American Journal of Respiratory and Critical Care Medicine Volume 190 Number 10 | November 15 2014
d Pulmonary function testing (PFT) andchest imaging (either a chest radiographor chest computed tomography scan) aretypically performed on any patient whoseBeLPT is diagnostic of BeS. In contrast,bronchoscopy with transbronchial biopsyis performed on a case-by-case basis.The following criteria favor performingbronchoscopy: (1) absence ofcontraindications, (2) evidence ofpulmonary function abnormalities, (3)evidence of abnormalities on chest imaging,and (4) personal preference of the patient.
d The diagnosis of CBD is based onthe demonstration of both BeS andgranulomatous inammation on lungbiopsy. Depending on the clinical setting,feasibility of certain diagnostic tests, anddegree of diagnostic certainty needed,probable CBD can be diagnosed basedon differing combinations of diagnosticcriteria, including a clinical presentationconsistent with CBD, a history ofberyllium exposure, evidence of BeS (e.g.,abnormal BeLPT), radiographic ndings,lung histology, BAL ndings, and PFTabnormalities.
d Periodic evaluation (every 13 yr) isperformed to determine if an individualwith BeS has progressed to CBD. Itincludes a symptom review, physicalexamination, and PFT, followed bya chest computed tomography scan ifpulmonary function has deteriorated andbronchoscopy on a case-by-case basis.
d Corticosteroid therapy is initiated whena patient with CBD exhibits signicantlung function abnormality or decline.Steroid-sparing agents are consideredif signicant side effects occur.
d Medical surveillance in workplaces thatuse beryllium-containing materials canidentify individuals with BeS and at-riskgroups of workers, which can helpprioritize the efforts to reduce inhalationaland dermal exposures. The BeLPT isthe cornerstone of medical surveillance.Individuals with beryllium exposure whodo not have BeS at the time of initialevaluation remain at future risk and maybenet from periodic BeLPTs.
Beryllium is a naturally occurring elementthat is extracted from ores and processedinto metal, oxides, alloys, and compositematerials. Industrial use of beryllium, such
as machining metal parts, can lead to BeSand CBD (1). The major applications ofberyllium are in automotive electronics,telecommunications, computers, aerospace,and defense equipment (Table 1). Onestudy estimated that as many as 134,000current U.S. workers may be exposedto beryllium (2), but the number ofindividuals ever exposed is much greater.Beryllium exposure is not a problemlimited to the United States, as cases ofCBD have been reported in many othercountries (310). Beryllium-exposedindividuals may be unaware of theirexposure, and physicians may be unawareof beryllium-related health effects; therefore,BeS and CBD may not be recognized.
This statement reviews currentknowledge about BeS and CBD, includingits diagnosis, management, and prevention.
The chair of the committee was selected bythe leadership of the American ThoracicSociety based on expertise and experience.The chair invited individuals to participatein the committee on the basis of theirexpertise in one or more aspects of BeSand/or CBD. Prospective members of thecommittee were required to disclose allnancial interests relevant to the subjectmatter of the statement. Disclosures werereviewed by the American Thoracic Societyprior to appointment of the committee, andappointments were made according toAmerican Thoracic Society policies formanagement of conicts of interest. Inaddition, individuals with conicts ofinterest related to the subject matter of thestatement acknowledged those conicts ina face-to-face meeting, stated that theywould not bias their participation on thecommittee, and were not assigned to workon sections of the document that addressedissues related to their conict.
Each member with primaryresponsibility for writing a section of thestatement searched the peer-reviewed, Englishlanguage medical literature using the NationalLibrary of Medicine MEDLINE databasethrough December, 2012. Additionalreferences were pursued that did not appearin the MEDLINE searches but were citedin the papers reviewed (Table 2). Individualarticles were appraised and then a writtensummary was prepared. The literaturesearches, study selections, and appraisals were
author directed. They did not conform to thestandards of a systematic review. Structureddiscussions were used to determine thecommittee members usual approach to thediagnosis and management of BeS and CBD.Variations in clinical practice were infrequentand minor; therefore, the approach describedreects the committees collective clinicalexperience in occupational health programs.
The committees work was partiallysupported by funds from the U.S.Department of Energy (DOE) and theNational Institute for Occupational Safetyand Health (NIOSH).
The rst cases of beryllium-related diseasewere identied soon after industrial useof beryllium began in the 1930s (1113).In the mid-1940s, reports of berylliumpoisoning in the United States appeared(14), including cases from the uorescentlight industry that had features of sarcoidosis(15). Additional cases appeared amongworkers employed in other beryllium-usingindustries as well as among individualsliving near beryllium production facilities(1618). The Atomic Energy Commissionestablished a beryllium case registry for bothacute disease and CBD (19, 20). The acutecases were observed among workers exposedto high levels of soluble forms of beryllium;however, the distribution of the chronicdisease did not follow a linear exposureresponse model. The high variability ofdisease occurrence in different groupsof workers, disease in workers with shortlatency, and incident disease in communityresidents led to the hypothesis that CBD wasimmunologically mediated (17).
In 1949, the Atomic En