Version May 2024
INTRODUCTION — Chronic beryllium disease (CBD), also called berylliosis, is a granulomatous disease caused by exposure to beryllium. Beryllium is an alkaline earth metal used in a number of different industrial applications. CBD shares many clinical and histopathological features with sarcoidosis and was first described in 1946 when 17 fluorescent lamp workers presented with a syndrome of advanced pulmonary granulomatous disease [1-3].
The pathogenesis, sources of exposure, clinical manifestations, diagnosis, and treatment of CBD will be reviewed here. The evaluation of the adult with interstitial lung disease and the clinical manifestations and diagnosis of sarcoidosis are discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Clinical manifestations and diagnosis of sarcoidosis".)
DEFINITIONS
●Chronic beryllium disease – A patient is considered to have CBD if all of the following are present [4]:
•A history of any beryllium exposure.
•A positive blood or bronchoalveolar lavage (BAL) beryllium lymphocyte proliferation test (BeLPT). (See 'Beryllium lymphocyte proliferation test' below.)
•Noncaseating granulomas and/or mononuclear cell infiltrates on lung biopsy; demonstration of BAL lymphocytosis and an abnormal BAL BeLPT are also considered to be indicative of granulomatous inflammation.
●Beryllium sensitization – A patient is considered to have beryllium sensitization when they have a positive BAL BeLPT and/or confirmed positive blood BeLPT, but no lung pathology. (See 'Beryllium lymphocyte proliferation test' below.)
RISK FACTORS
High risk occupations — Beryllium, which is lighter than aluminum and six times stronger than steel, is often alloyed with copper, aluminum, and nickel [5,6]. Exposure to beryllium may occur among workers in the following industries [4,7-10]:
●Heavy beryllium-using industries: metal and metal alloy (beryllium-copper) machine shops, electronics, defense industry, and beryllium extraction
●Other beryllium-using industries: automotive, ceramic, computer, aerospace, metal reclamation, electronics and computer recycling, jewelry making, and dental alloy/appliance
●Construction and shipyard industries: mostly associated with abrasive blasting operations and welding
Dose and duration of exposure — The exact exposure-response relationship for CBD is unclear. Both the dose and duration of beryllium exposure appear to be associated with an increased risk of sensitization and disease, with rates as high as 20 percent in certain higher exposure work tasks (eg, beryllium ceramics, machining, rod and wire production) [8,11-15]. However, while the relationship does not appear to be linear, increasing exposure is associated with increasing risk of CBD [16], and the overall rate of CBD appears to be between 1 and 7 percent, according to cross-sectional studies of beryllium-using workplaces [8,9,11-15,17-23].
●Workplace exposure – The current United States Occupational Safety and Health Administration (OSHA) industrial exposure limit for airborne beryllium is 0.2 mcg/m3 time weighted average exposure for an eight hour day with a short term exposure limit of 2 mcg/m3 over a 15 minute sampling period. OSHA also implemented an action level of 0.1 mcg/m3 along with medical surveillance for workers who are regularly exposed above this level [24]. While this revised OSHA standard should prevent a number of cases of CBD, it will likely not prevent all, as CBD still can occur at exposure levels lower than those currently proposed in the new OSHA standard [16,25-27]. (See 'Prevention' below.)
The prior OSHA level of 2 mcg/m3 over eight hours was not protective against CBD [7,9,11-13,15,19-21,23]. Some individuals develop clinically significant illness even at extremely low levels of exposure or after an exposure as short as three months [17]. Examples include those working in decontamination and decommission of old buildings in which beryllium had been used, construction trade workers, security guards, and secretaries [8,9,18,22,28]. It is estimated that between 134,000 and 800,000 current and former workers have been exposed to beryllium in the United States, although this number is likely an underestimate [29]. The problem is not confined to the United States; cases of CBD have also been reported elsewhere in North America, South America, Europe, and Asia [7].
●Community-acquired CBD – Community-acquired CBD has also been described in a small number of residents living within five miles of beryllium manufacturing facilities [30]. In a community survey of residents without occupational exposure to beryllium, disease manifestations sometimes developed 19 to 52 years after community-based exposure had ceased and were associated with substantial morbidity. Nonoccupational cases of CBD have been described in family members of beryllium workers, through second-hand exposure [31]. One case of community-acquired CBD was caused by environmental exposure to beryllium-containing concrete dust from a nearby concrete factory; five additional work colleagues showed beryllium sensitization in this setting [28].
PATHOGENESIS — The pathogenesis of CBD appears to involve a combination of an immunologic response to beryllium exposure and an underlying genetic susceptibility [10], although the reasons for persistence and progression of lung disease following cessation of exposure are less clear. Inhaled beryllium particles can be retained in the lungs, particularly within CBD granulomas, for years after cessation of beryllium exposure [32].
●Immunologic response – In patients with CBD or beryllium sensitization, beryllium elicits an immunologic reaction with characteristics of a cell-mediated or delayed hypersensitivity reaction [33-35] (see "Normal B and T lymphocyte development" and "The adaptive cellular immune response: T cells and cytokines"). These characteristics include beryllium-specific sensitization of T cells, proliferation of T cells upon re-exposure, production and release of proinflammatory cytokines, and granulomatous inflammation [10]. As the lungs are the typical portal of entry of beryllium, it is not surprising that the immune response is most strongly evident in the lungs.
Studies of peripheral blood lymphocytes isolated from patients with CBD have shown that re-exposure to beryllium in vitro typically induces a proliferative response [36]. This proliferative response is specific for beryllium and is not induced by other metals. (See 'Beryllium lymphocyte proliferation test' below.)
Similarly, studies of mononuclear cells obtained by bronchoalveolar lavage (BAL) from patients with CBD support the immunologic role of beryllium in the pathogenesis of CBD. The BAL cells were found to be relatively rich in CD4+ T cells that proliferated when cultured in vitro with beryllium salts [37]. This T cell proliferative response could be abrogated with antibodies directed to major histocompatibility complex (MHC) II, but not MHC I [37]. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Constituents of BAL in ILD'.)
The beryllium cations interact with host proteins, such as the transmembrane protein plexin A4 and the chemokines, C-C motif ligand 4 (CCL4) and CCL3, to create neoantigens that are the major antigenic targets in CBD [38-40]. The CCL3/4-Be neoantigen on the surface of antigen-presenting cells is recognized by CD4+ T cells expressing a susceptible human leukocyte antigen [HLA]-DP2-peptide complex [41]. These findings as well as the potential for enhanced antigenic potency of beryllium protein complexes provides a potential mechanism to explain how extremely low environmental levels of beryllium exposure in the workplace can induce sensitization and disease [42].
Lung mononuclear cell inflammation and granuloma formation are presumably maintained by the accumulation in the lung of large numbers of CD4+ memory T cells specific for either beryllium itself, beryllium associated with HLA-DP or HLA-DR, and as noted above, likely beryllium bound to an endogenous peptide (eg, plexin A4, CCL3, CCL4) [38,39]. Beryllium sensitization is predominantly a Th1 response involving interferon gamma and interleukin-2 [43]. In addition, cells collected by BAL from patients with CBD express increased levels of tumor necrosis factor-alpha and interleukin-6 [44]. These cytokines (in conjunction with T cell cytokines) are thought to be important in the initiation and maintenance of the human granulomatous response [45].
Several hypotheses have been developed to explain why CBD persists and progresses after removal from exposure to beryllium. One possibility is that the metal antigen is retained in the lung due to the solubility of beryllium and its ability to cause macrophages to undergo apoptosis and re-release previously phagocytosed beryllium particles [32,46]. Another potential explanation comes from the identification of a deficient and dysfunctional population of regulatory T (Treg) cells in the BAL fluid obtained from patients with CBD [47]. The impaired functional capacity of the Treg cells may decrease the suppression of CD4+ T cell proliferation. Furthermore, the identification of self-peptide as a potential antigen and conformational change of the MHC structure induced by beryllium suggest that autoimmunity may also contribute. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Suppression'.)
●Genetic susceptibility – HLA disease associations and susceptibility to abnormal immune reactions are believed to reflect changes in the HLA molecule hypervariable regions critical to antigen presentation [48]. In this regard, the HLA-DPbeta1 (HLA-DPB1) gene comprises six hypervariable coding regions. Eighty-five percent of patients with CBD (compared with 40 to 45 percent of controls) have an HLA-DPB1 variant (E69), which contains a glutamate for lysine substitution at position 69 at one of the hypervariable regions [16,25,49-52]. This variant along with other amino acid changes in the antigen binding pocket results in a markedly increased risk of CBD [53]. HLA-DRB1 variants with similar negatively charged amino acids (glutamate at position 71) in the antigen binding pocket have been shown to be associated with CBD risk, particularly in those individuals who do not have the HLA-DP DPB1 glutamate 69 variant [35]. (See "Human leukocyte antigens (HLA): A roadmap", section on 'Class II region'.)
At present, these genotypes are markers for susceptibility to beryllium sensitization and CBD among exposed individuals. However, they are not appropriate screening tools given the relatively high prevalence of these genotypes in the general population [49,50,52,54,55]. Similarly, tumor necrosis factor (TNF)-alpha polymorphisms have been associated with beryllium-induced expression of TNF-alpha messenger RNA and protein by CBD patients' blood and BAL cells, but not with CBD or risk of beryllium sensitization [56-58]. Additional genetic factors are likely involved in the risk of beryllium sensitization, progression to CBD, and more severe disease, although these are unclear at this time. Studies of gene by environment interactions demonstrate that both beryllium exposure and HLA-DPB1 genotype contribute to the odds of developing beryllium sensitization and CBD [16,26,59]. This information is important as exposure should be reduced to protect the most susceptible population [16].
CLINICAL MANIFESTATIONS — The clinical manifestations of CBD are nonspecific [60]. Dry cough and shortness of breath are common symptoms; fever, night sweats, fatigue, and weight loss are seen less often [9,47]. Bronchial involvement can produce symptoms similar to those of asthma. The latency period between initial beryllium exposure and onset of symptoms varies from three months to 30 years [15].
Cutaneous nodules can develop, especially if beryllium has penetrated the skin (picture 1). These nodules tend to be located on exposed areas of skin, such as fingers and forearms and are generally smaller than the cutaneous nodules seen in sarcoidosis. Pulmonary examination is more likely to reveal bibasilar crackles in more advanced disease [47,61]; similarly, cor pulmonale and digital clubbing are associated with advanced disease.
EVALUATION — CBD should be suspected in any patient in an occupation that involves beryllium exposure who presents with dyspnea or evidence of interstitial lung disease (ILD) (see 'High risk occupations' above). The evaluation of patients with suspected CBD includes identifying beryllium sensitization of peripheral blood and bronchoalveolar cells with beryllium lymphocyte proliferation testing, assessing the severity of disease with pulmonary function testing, determining whether the pattern seen on chest imaging is compatible with CBD, and confirming the diagnosis with histopathologic analysis. Our approach to the evaluation of suspected CBD is described in the algorithm (algorithm 1).
Laboratory testing — Routine laboratory tests are typically nonspecific. Laboratory testing for other types of interstitial lung disease (eg, rheumatic disease, eosinophilic lung diseases, vasculitis) should follow the usual guidelines (table 1). (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Laboratory testing'.)
A blood beryllium lymphocyte proliferation test (BeLPT) is the most appropriate initial test for suspected CBD [4]. (See 'Beryllium lymphocyte proliferation test' below.)
Measurement of the serum angiotensin converting enzyme (ACE) level is not helpful, as it does not discriminate between patients with CBD, beryllium sensitization, beryllium exposure, or sarcoidosis [62]. Among 23 patients with CBD, only 22 percent had an elevated serum ACE level [62]. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Proposed activity tests, including angiotensin converting enzyme (ACE) level'.)
A tuberculin skin test or interferon-gamma release assay (IGRA) may be performed in patients being evaluated for CBD to exclude tuberculosis (TB). (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)
As in other granulomatous diseases of the lung, increased production of calcitriol (the most active form of vitamin D) by activated pulmonary macrophages can lead to hypercalciuria and hypercalcemia [60]. (See "Hypercalcemia in granulomatous diseases".)
Beryllium lymphocyte proliferation test — The blood BeLPT is the most appropriate initial test for patients suspected of having CBD and has become the standard industry surveillance tool for identifying beryllium-sensitization among beryllium-exposed workers [4,31,37,63]. Repeated testing with the BeLPT is used to detect workers who may develop sensitization or CBD over time and is recommended for monitoring of those with ongoing exposure. The BeLPT is also used to correct misdiagnoses of sarcoidosis [2,64].
In the BeLPT assay, mononuclear cells from peripheral blood or bronchoalveolar lavage (BAL) are exposed in vitro to three different concentrations of beryllium salts (eg, beryllium sulfate) for two different time intervals [65]. Cell proliferation is measured by the incorporation of tritiated thymidine into the DNA of dividing cells. The cutoff value for a positive test is laboratory-dependent. If none of the six resultant tests show increased lymphocyte proliferation, the test is normal. If one of the six incubations shows increased uptake, the test is borderline. If two or more of the incubations show increased uptake the test is abnormal. The specificity of in vitro generated beryllium-reactive cells can be demonstrated by the lack of response to other metals and by the normal stimulation index of those exposed to beryllium without evidence of disease [37,66,67].
The sensitivity of a single peripheral blood BeLPT is 0.683 and the specificity 0.96 [68]. To improve the sensitivity of the testing and to resolve borderline test results, all negative and borderline tests are generally repeated [63,65]. If the second test is either positive or borderline, the patient is considered to be sensitized to beryllium [65]. Among patients with a positive blood BeLPT, 20 to 100 percent will have evidence of CBD based on BAL or transbronchial biopsy results [7,13,15,17,69]. This wide range is likely related to variations in the magnitude of beryllium exposure in the workplace [70].
On the other hand, if both rounds of BeLPT testing are negative, the patient may still have CBD, as the probability of having two false negative results is estimated to be between 7 and 10 percent. Thus, for an individual with clinical evidence of lung disease and a history of exposure to beryllium, even at very low levels, further testing for CBD (eg, BAL, tissue biopsy) would be indicated even if the blood BeLPT is negative.
If BeLPT testing is not available locally, blood and BAL samples are sent to a reference laboratory (eg, National Jewish Health, Cleveland Clinic, or ORISE Beryllium Testing Laboratory).
●Experimental testing methods – Experimental variations on the BeLPT have been developed in an effort to improve detection of lymphocyte proliferation. Some of these tests use flow cytometry to assess lymphocytes that have entered cell cycle upon stimulation with beryllium salts [42,71,72]. A separate investigational approach monitors in vitro macrophage production of neopterin following beryllium stimulation, as an indicator of beryllium-induced tumor necrosis factor (TNF)-alpha and gamma interferon activation. Although this modification of the blood BeLPT may eventually help differentiate beryllium sensitization from CBD, it requires further investigation [73].
Another experimental approach to distinguishing between beryllium sensitization and CBD without invasive procedures, called a beryllium ELISPOT test, assesses the number of beryllium-specific CD4+ T cells in the peripheral blood. Patients with CBD tend to have higher numbers of these circulating beryllium-specific T cells than subjects with sensitization alone; however, the accuracy and predictive value of the beryllium ELISPOT test remain under investigation [74-76].
Chest imaging — Chest radiographs are generally obtained in patients suspected of having CBD. Depending on the time course and severity of disease, the chest radiograph may be normal or may show hilar adenopathy or parenchymal abnormalities such as nodules, ground glass, linear, or alveolar opacities. The parenchymal abnormalities may be diffuse or may be more prominent in the upper lobes.
High-resolution computed tomography (HRCT) is more sensitive than a plain chest radiograph in identifying the changes of CBD, although HRCT is normal in up to 25 percent of patients with biopsy-proven CBD [77]. The HRCT findings associated with CBD include parenchymal nodules of varying size (eg, peribronchial interlobular septa, subpleural), thickened septal lines, ground glass opacities, cystic cavitation, bronchial wall thickening, and adenopathy involving the hilum or mediastinum [61,78,79]. Hilar lymphadenopathy develops later in the course of CBD compared with sarcoidosis [61]. Pleural thickening may be observed adjacent to areas of dense subpleural parenchymal nodules, but pleural effusions are uncommon. Pneumothorax has been reported [79]. (See "High resolution computed tomography of the lungs".)
Pulmonary function tests — Pulmonary function tests are obtained in virtually all patients suspected of having CBD on the basis of dyspnea, an abnormal chest radiograph, or a history of exposure to beryllium. (See "Overview of pulmonary function testing in adults".)
Early in the course of CBD, the pulmonary function abnormalities, if present at all, include mild airflow limitation and abnormal gas exchange at rest or during exercise (manifested as worsening hypoxemia with increasing exercise). The diffusing capacity for carbon monoxide (DLCO) is commonly diminished, although this test is less sensitive than measurements of gas exchange at rest and exercise (eg, pulse oximetry and/or arterial blood gas measurements). As the disease becomes more clinically apparent, spirometry shows airflow limitation, restriction, or a mixed pattern. Pure restriction is a relatively late finding [80].
Flexible bronchoscopy
Bronchoalveolar lavage — For patients who have a positive peripheral blood BeLPT or a clear history of exposure to beryllium and suspected ILD, we perform bronchoscopy with a BAL to obtain cell counts and a sample of BAL mononuclear cells for BeLPT testing [4]. As BeLPT requires special handling of BAL fluid and is only performed by a few laboratories, it is essential to communicate with the laboratory prior to obtaining the specimen. As an example, blood and BAL fluid can be sent by overnight courier to one of the centers that perform this specialized assay on a regular basis, such as National Jewish Health, the Cleveland Clinic, and the Oak Ridge Institute for Science and Education (ORISE).
●Specialized procedure for BAL BeLPT – The technique for obtaining BAL fluid for BeLPT testing differs from the usual BAL technique due to the requirement for a large number of cells. The exact specifications for preparation and transportation of the BAL cells for BeLPT may vary between laboratories and should be confirmed with the laboratory prior to performing the BAL. During bronchoscopy, the BAL is performed prior to any biopsy procedures to avoid contamination of the fluid with blood from a biopsy. After wedging the bronchoscope in an area of lung believed to have active disease based on the HRCT, typically four successive 60 mL saline lavages are done to a total instilled volume of 240 mL. If the lung is diffusely involved, the BAL is performed in either the lingula or right middle lobe. If the return from the lavage is less than 50 percent, an additional lavage may be performed in a separate site. (See "Basic principles and technique of bronchoalveolar lavage", section on 'Technique'.)
After samples for other studies have been set aside, the BAL fluid is centrifuged at approximately 1200 RPM for 10 minutes. The supernatant is discarded, and the cells are resuspended in a plastic centrifuge tube with a mixture of RPMI 1640 (or similar tissue culture medium), gentamicin sulfate or penicillin/streptomycin (0.5 percent by volume), and pooled AB positive serum or the patient's own serum at 10 percent by volume. The final concentration of cells in the media should be approximately 5 to 10 million cells per mL. The sample is kept at room temperature and transported immediately to the laboratory performing the BeLPT test.
●Interpretation of BeLPT – Approximately 10 to 35 percent of patients with beryllium sensitivity have a negative BeLPT test on peripheral blood, but a positive test on BAL mononuclear cells [68]. One explanation for this observation is that cells obtained from BAL generally yield higher peak stimulation responses to beryllium salts than cells from peripheral blood [81]. However, occasionally BAL proliferation assays give false negative results due to a significant excess of alveolar macrophages in the lavage, which is a common finding among cigarette smokers [37]. (See 'Beryllium lymphocyte proliferation test' above.)
When the BeLPT on BAL lymphocytes is positive, but transbronchial biopsies are inadequate or cannot be obtained, BAL lymphocytosis may be used as a surrogate marker for underlying pathology. BAL lymphocytosis is usually defined as greater than 20 percent lymphocytes (the 95 percentile for never smokers) [4]. However, BAL lymphocytosis is not specific for CBD, unless a BAL BeLPT is positive. For patients with BAL lymphocytosis and a negative BAL BeLPT, further evaluation for other causes of BAL lymphocytosis is needed (table 2). (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Role of bronchoalveolar lavage' and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Lymphocytic BAL'.)
●Standard testing of BAL fluid – In general, the BAL cell count shows lymphocytosis with values greater than 20 percent [4,82]. A portion of the BAL fluid should be sent for cytology and cultures (eg, actinomycosis, nocardia, mycobacteria, fungi). (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Basic principles and technique of bronchoalveolar lavage", section on 'Processing the lavage specimen'.)
Endobronchial and transbronchial biopsy — Endobronchial and transbronchial biopsies are usually obtained at the time of flexible bronchoscopy to fulfill the third criterion for CBD diagnosis [4]. Endobronchial biopsies are useful because noncaseating granulomas have been identified in the bronchial wall in approximately thirty percent of patients with CBD [83]. Four to six endobronchial biopsies are typically obtained from a site where the mucosa appears erythematous; if the mucosa appears normal throughout, endobronchial biopsies are obtained from the main carina and a secondary carina [84]. (See "Flexible bronchoscopy in adults: Overview" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Endobronchial brushing'.)
Transbronchial biopsies are typically obtained from an area of involved lung (identified by the HRCT scan appearance), but not the same site as a BAL performed during the same procedure. Typically, 8 to 10 transbronchial biopsy pieces (as tolerated by the patient) are obtained to maximize the yield [85]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy' and "Flexible bronchoscopy in adults: Overview" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)
Histopathology — When preparing samples from transbronchial lung biopsies for histopathologic analysis, at least 10 sections should be made from the tissue block in order to reduce the chance of missing granulomas [85]. The typical pathologic findings of CBD are noncaseating granulomas and/or mononuclear cell infiltrates in the bronchial wall or lung interstitium. In some patients, the same pathology can be detected in the regional lymph nodes [83,86]. Biopsies of beryllium-induced skin nodules also typically demonstrate noncaseating granulomas.
While it is possible to measure beryllium inside granulomas using mineral analytic methods that can demonstrate increased levels of beryllium within granulomas, this testing is not commonly used to diagnose CBD [32].
Among patients with clinical evidence of CBD based on exposure history and pulmonary function testing or HRCT, approximately 5 to 10 percent have false-negative biopsies and require either repeat bronchoscopy or, rarely, video-assisted thoracoscopic lung biopsy. False negative results should be suspected if the lavage lymphocyte percentage is elevated (eg, >20 percent in nonsmokers) and the BeLPT is positive on either the blood or BAL samples [85].
DIAGNOSIS — The definitive diagnosis of CBD requires that all three of the following findings be present [4]:
●History of beryllium exposure – Even seemingly minor or historically-remote exposures to beryllium or its alloys can be significant. (See 'Risk factors' above.)
●Positive beryllium lymphocyte proliferation test – A positive peripheral blood or bronchoalveolar lavage (BAL) beryllium lymphocyte proliferation test (BeLPT) is needed to document sensitization. (See 'Beryllium lymphocyte proliferation test' above.)
●Compatible histopathology – Noncaseating granulomas and/or mononuclear cell interstitial cell infiltrates on endobronchial or transbronchial biopsy are needed to confirm the diagnosis. (See 'Endobronchial and transbronchial biopsy' above.)
When histopathology is unavailable or negative, a clinical diagnosis of CBD can be made based on the history of exposure, BAL lymphocytosis (>20 percent) with a positive BAL BeLPT, and imaging that shows abnormalities consistent with CBD. (See 'Definitions' above.)
The United States Department of Labor (DOL) has specific diagnostic criteria for current or former workers at Department of Energy (DOE) facilities applying for compensation due to a diagnosis of CBD [87].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CBD includes sarcoidosis, hypersensitivity pneumonitis, granulomatous vasculitides, mycobacterial infection, and other granulomatous lung diseases (eg, due to other metals like aluminum or titanium and drug-induced hypersensitivity) [4]. The key differentiating feature is the beryllium-specific immune response. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Granulomatous lung diseases'.)
●Sarcoidosis – Due to the strong clinical and histopathological resemblance of sarcoidosis and CBD, patients are sometimes misdiagnosed with sarcoidosis until the history of exposure to beryllium is elicited and beryllium hypersensitivity demonstrated with specific testing [88]. As an example, it is estimated that up to 6 percent of all patients diagnosed with sarcoidosis may actually have CBD, although the exact proportion depends on the clinic's referral population and the degree of clinical suspicion [2,3]. Among patients diagnosed with sarcoidosis in whom beryllium exposure can be confirmed, as many as 40 percent may actually have CBD. Of note, extrapulmonary disease is much more common in sarcoidosis than in CBD. (See 'Beryllium lymphocyte proliferation test' above and "Clinical manifestations and diagnosis of sarcoidosis".)
●Hypersensitivity pneumonitis – Hypersensitivity pneumonitis should be suspected in patients with known exposure to a causative agent of HP and those with clinical and imaging evidence of interstitial lung disease without specific features to suggest an alternate diagnosis. Compared with granulomas in sarcoidosis and berylliosis, granulomas in hypersensitivity pneumonitis tend to be smaller, less discrete, and surrounded by more interstitial lymphocytic inflammation. However, chronic HP may be indistinguishable from other fibrosing interstitial pneumonias in biopsy specimens. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)
●Granulomatous vasculitides – Granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis have an angiocentric pattern of inflammation and associated evidence of vasculitis that differentiate them from other pulmonary granulomatous diseases. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement" and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)
GENERAL MANAGEMENT — All patients with CBD should be advised to avoid further exposure to beryllium. Supportive care is provided based on symptoms and degree of respiratory impairment. Therapy with glucocorticoids or other immunosuppressive agents depends on the severity of symptoms, physiologic impairment, and radiographic involvement.
Avoidance of beryllium exposure — All patients with CBD should be removed from further exposure to beryllium to the extent possible [16,26,89,90]. For individuals identified as having beryllium sensitization without CBD (see 'Definitions' above), avoidance of further exposure is advised to avoid progression to CBD. This advice is based on studies demonstrating that CBD is associated with higher average and cumulative exposures than those with beryllium sensitization alone [16,26,83,89]. Individuals with beryllium sensitization or with subclinical CBD should be monitored periodically for evidence of disease progression, given the often slow rate of progression and latency of CBD.
Supportive therapy — Although not specifically studied in patients with CBD, supportive therapies, such as influenza and pneumococcal vaccination and smoking cessation counselling, are provided to all patients. Supplemental oxygen and pulmonary rehabilitation are prescribed as indicated. (See "Long-term supplemental oxygen therapy", section on 'Indications' and "Pulmonary rehabilitation" and "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults", section on 'Approach to vaccination'.)
ASYMPTOMATIC OR MILD DISEASE — Patients with mild CBD who are asymptomatic or have mild exertional dyspnea and normal or near normal pulmonary function can be observed for stabilization or improvement with beryllium avoidance. In early disease, treatment with inhaled corticosteroids (ICS) has been shown to improve symptoms of cough and dyspnea especially in patients with obstruction and air trapping [91].
SYMPTOMATIC DISEASE OR IMPAIRED LUNG FUNCTION — Patients with symptoms or significant decrements in pulmonary function should generally receive adjunctive therapy in addition to cessation of beryllium exposure.
Initial treatment with glucocorticoids — Systemic glucocorticoid therapy is the standard treatment for symptomatic CBD with evidence of respiratory impairment on pulmonary function tests [4,47]. While glucocorticoid therapy has not been evaluated in controlled clinical trials of patients with CBD, clinical experience is strongly supportive. (See 'Efficacy' below.)
Patient selection — For most patients, we suggest systemic glucocorticoid treatment when the patient reports bothersome dyspnea or cough; when baseline pulmonary function testing reveals evidence of significant lung volume or alveolar loss (eg, vital capacity, lung volumes, or diffusing lung capacity for carbon monoxide [DLCO] less than 70 percent of predicted); or when there has been a decline in lung volumes or gas exchange by greater than 10 percent predicted despite cessation of beryllium exposure [89]. The decision to treat with prednisone requires balancing the medication's potential benefits against the patient's risk of adverse effects such as diabetes mellitus, hypertension, osteoporosis, and increased susceptibility to infection. (See 'Administration' below.)
Patients with beryllium sensitization in the absence of CBD do not require treatment, but should undergo biennial evaluation for progression into CBD [89]. Patients who have documented CBD, but minimal or absent symptoms and physiologic abnormalities, also do not require active treatment, but are reassessed at 6 to 12 month intervals. (See 'Asymptomatic or mild disease' above.)
Administration — When prescribing prednisone for CBD, the usual initial dose is between 20 and 40 mg per day or 40 mg every other day [4,47,90]. Approximately 6 to 12 weeks after initiating prednisone, the patient's symptoms, spirometry, lung volumes, and gas exchange (eg, DLCO, arterial blood gases, pulse oxygen saturation at rest and on exertion) are reassessed. Once a clinical response is noted, the dose of prednisone is tapered to as low a dose as possible to maintain improvement in lung function. Gas exchange abnormalities may be followed for treatment response every three to six months depending on the clinical setting. Chest imaging may or may not demonstrate improvement.
●Tapering – Evaluations are repeated at approximately three month intervals, and the dose of prednisone is gradually tapered to the lowest level needed to maintain physiologic and symptomatic improvement and disease stability, usually about 5 to 10 mg daily, or the equivalent. Complete withdrawal of prednisone can result in disease recrudescence, so lifelong therapy is usually continued at the lowest dose of prednisone that controls disease manifestations [89,92]. In one series, eight patients were treated with glucocorticoids for a median of 69 months (range 20 to 180). Seven of these eight patients experienced a clinical relapse as the treatment was tapered [47]. Interestingly, the three patients with Glu69 homozygosity (human leukocyte antigen [HLA]-DPB1 genes coding for glutamate at position beta69) experienced multiple relapses (11 of the 18 total relapses seen in the cohort). (See 'Pathogenesis' above.)
●Adverse effects – Long-term therapy with systemic glucocorticoids is associated with a number of potential adverse effects, including osteoporosis, increased susceptibility to infection, weight gain, cataract formation, and adrenal suppression. Monitoring and prevention of adverse effects of glucocorticoid treatment are discussed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Major adverse effects of systemic glucocorticoids", section on 'Organ-based toxicity of systemic glucocorticoids'.)
Efficacy — The response to glucocorticoid therapy has been documented in case reports and case series for more than 40 years, making it the standard treatment for CBD [4,47,60,89,93]. As an example, in a series of eight patients with CBD and nodules, micronodules with hazy borders, or ground glass opacities on high resolution computed tomography (HRCT), all patients experienced symptomatic and radiographic improvement with glucocorticoid therapy [47]. By 12 months, lung volumes had improved in all patients; diffusing capacity had improved in seven; and the arterial partial pressure of oxygen (PaO2) had improved in seven. In two patients who had initial improvement with glucocorticoid therapy, subsequent deterioration in lung function occurred, accompanied by progression of fibrosis on the HRCT. In a separate series, seven symptomatic patients were treated with systemic glucocorticoids; two improved, four had stable, but persistent disease, and one died [79].
The efficacy of glucocorticoid therapy may be improved by initiating therapy before fibrotic disease becomes established. As an example, in a small series, the patients who responded to glucocorticoid therapy had a time interval from onset of symptoms to initiation of therapy of 1.1 years and those who did not respond had an interval of 9.9 years [90].
Refractory disease — Despite the overall favorable impression of glucocorticoid therapy for CBD, not all patients respond [47,90]. In some cases failure to respond is due to ongoing exposure to beryllium, in others, to delayed removal from exposure and delayed initiation of therapy [90]. If no improvement in symptoms or physiologic parameters has occurred after six months, a decision is made whether to discontinue glucocorticoid therapy or add another immunosuppressive agent. If there has been a lag time of several years between the onset of symptoms and initiation of therapy or if the chest radiograph and HRCT suggest a greater proportion of fibrotic change, the patient likely does not have reversible disease and glucocorticoid therapy can be tapered and stopped. If the clinical impression supports a greater likelihood of reversible disease, an additional immunosuppressive agent is usually added.
Other immunosuppressive agents — For patients who fail to respond to glucocorticoids or who experience adverse effects, addition of alternative immunosuppressive agents may be tried, although clinical trials supporting their use have not been published. Based on the experience with low-dose methotrexate therapy for sarcoidosis, this agent is often chosen for refractory CBD [85]. Prior to initiating methotrexate, liver function tests and hepatitis B and C viral antibody testing are obtained. Patients with evidence of underlying liver disease or chronic infection with hepatitis B or C are not candidates for methotrexate. In addition, ingestion of alcoholic beverages while using low-dose methotrexate is strongly discouraged, and patients who are unwilling to reduce their alcohol consumption to an occasional and minimal level are not treated with methotrexate. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Patients who progress on or do not tolerate glucocorticoids' and "Major side effects of low-dose methotrexate".)
Oral methotrexate is usually initiated at a starting dose of 7.5 to 10 mg weekly and gradually increased (eg, by 2.5 mg increments every two weeks) until a dose of 15 mg per week is achieved. Folic acid 1 mg daily is routinely given to patients taking chronic low-dose methotrexate therapy. Methotrexate toxicity includes liver inflammation and fibrosis, bone marrow suppression, alopecia, skin rash, gonadal suppression, and teratogenicity. Complete blood counts and liver tests (eg, aminotransferases and albumin) are repeated at 4 to 8 week intervals while escalating the dose and then at 8 to 12 week intervals. After a stable dose is achieved (usually by six months of therapy), most clinicians obtain liver tests every 12 weeks. (See "Major side effects of low-dose methotrexate".)
Azathioprine is another potential adjunctive therapy to glucocorticoids, given some success with this agent in patients with sarcoidosis [89,94]. However, no published data are available to support this choice. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Azathioprine'.)
Based on the current understanding of immunopathogenesis of CBD, tumor necrosis factor (TNF)-alpha antagonists appear promising as therapeutic agents. However, only one small clinical trial has been conducted. Similar to the findings in sarcoidosis, this trial suggests that those with more severe disease may experience improvement in quality of life and potentially also lung function [95]. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Tumor necrosis factor-alpha antagonists'.)
Lung transplantation — Lung transplantation has been performed for advanced CBD and respiratory failure, but outcomes have not been formally studied [4]. A case report of lung transplantation in a patient with end stage CBD demonstrated allograft complications and development of bronchiolitis obliterans syndrome resulting in death seven years post-transplant [96].
FUTURE DIRECTIONS — Preliminary research suggests a possible role for 5-aminosalicylic acid (ASA) in the management of mild-to-moderate CBD. In a study of 17 patients randomly assigned (3:1) to 5-ASA or placebo for six weeks, bronchoalveolar lavage (BAL), but not blood, beryllium lymphocyte proliferation test (BeLPT) decreased by 20 percent and quality of life improved [97,98].
PROGNOSIS — CBD has a variable clinical course [4]. Published mortality rates range from 6 to 35 percent [89,99]. The variability appears to depend on the industrial setting, the duration of beryllium exposure after development of CBD, individual variation, and the duration of clinical follow up. As an example, beryllium extraction workers appear to have a lower mortality rate than those working with beryllium alloys or ceramics [99]. The reason for this observation is not known.
Among patients with beryllium sensitization without CBD (ie, a positive blood beryllium lymphocyte proliferation test [BeLPT], but no lung pathology), the risk of progressing to CBD is clearly increased, compared with non-sensitized workers. The magnitude of risk was evaluated in a longitudinal study of 55 sensitized individuals, 17 of whom (31 percent) developed CBD within a median follow-up of 3.8 years [83]. In a separate surveillance study, progression from beryllium sensitization to CBD occurred in 9 percent [100].
Whether the disease will be mild or fulminant is not predicted by the duration of exposure or the degree of positivity of the peripheral blood BeLPT. However, the type or intensity of exposure may influence progression as suggested by a surveillance study that found a higher rate of disease progression among machinists than non-machinists based on pulmonary function and gas exchange testing [100]. In addition, a higher percentage of lymphocytes in the bronchoalveolar lavage (BAL) correlates with a greater severity of the illness [101]. Tobacco use does not seem to predict a worsened clinical course, and in some studies smokers with beryllium sensitization of peripheral blood lymphocytes were less likely to have CBD at the time of bronchoscopy [9,83].
For patients with CBD who receive treatment with glucocorticoids, stabilization or improvement in symptoms and pulmonary function is likely, as long as glucocorticoid therapy is maintained. However, some patients experience progressive deterioration in lung function and development of pulmonary fibrosis, despite cessation of beryllium exposure and maintenance glucocorticoid therapy [47,90].
Beryllium has been suspected of increasing the risk of lung cancer [102]; however, studies with careful adjustment for the risk attributable to cigarette smoking have not supported a significant increase in risk due to beryllium exposure [103-106].
PREVENTION — In 2020, the United States Occupational Safety and Health Administration (OSHA) published a new permissible exposure limit (PEL) that was 10-fold lower than prior at 0.2 mcg/m3 with a short-term exposure limit of 2 mcg/m3 over a 15-minute sampling period [10,24]. In addition, they included an action level of 0.1 mcg/m3 and medical surveillance with the BeLPT for workers exposed above the action level for 30 days in a year or shows signs or symptoms of CBD. As noted above, this new OSHA standard is likely to prevent some, but not all cases of CBD, as CBD still can occur at exposure levels lower than the proposed new OSHA standard [25-27]. (See 'Risk factors' above.)
The lines of evidence to support the new, lower permissible exposure limit are thoroughly described in the 2020 revised OSHA Final Rule [24]. As an example, in a study of workers in a beryllium machining facility, workers who developed beryllium hypersensitivity or CBD were exposed to beryllium concentrations in the ambient air above 0.2 mcg/m3 (95th percentile) [107]. Among workers at the facility who developed CBD, 90 percent were exposed to concentrations greater than 0.4 mcg/m3 within a given year of their work history. Based on this analysis, it was suggested that maintaining exposure levels below 0.2 mcg/m3 for 95 percent of the time might prevent beryllium sensitization and CBD. Further work is needed to determine a level of exposure to beryllium that is safe for all workers, including those with a greater susceptibility or genetic predisposition, as they appear to develop disease at a level lower than others [16,26].
There are a number of ways to minimize occupational exposure to beryllium. These include having companies use safer metals, improving ventilation systems to reduce dust, administrative controls such as minimizing the number of workers allowed into beryllium areas, providing personal protective equipment (eg, respirators) when exposures cannot be adequately controlled, and educating workers in how to reduce the risk of exposure [20]. Dermal exposure can also contribute to risk of beryllium sensitization; therefore, measures should be taken to protect skin [108,109]. Use of the beryllium lymphocyte proliferation test (BeLPT) in the workplace is now mandated by OSHA for exposed workers and can potentially identify areas associated with a greater risk for CBD or sensitization.
SUMMARY AND RECOMMENDATIONS
●Definition – CBD, also called berylliosis, is caused by exposure to respirable beryllium metal or alloys and is characterized by the presence of noncaseating granulomas in the lungs. CBD shares many clinical and histopathological features with pulmonary sarcoidosis. (See 'Definitions' above.)
●Risk factors – Beryllium exposure occurs in various industries, including beryllium and beryllium alloy (beryllium-copper) machining and the aerospace, automotive, ceramics, computer, defense, electronic, and metal recycling industries. Beryllium exposure also occurs in the construction and shipyard industries, mostly associated with abrasive blasting operations. Community-acquired CBD has also been described. (See 'Risk factors' above.)
●Evaluation – Our approach to the evaluation and diagnosis of CBD is described in the algorithm (algorithm 1).
•Clinical manifestations – In a patient with a history of beryllium exposure, the diagnosis of CBD should be suspected in the presence of dyspnea, cough, or a chest radiograph showing hilar adenopathy or reticular and nodular lung opacities. (See 'Clinical manifestations' above and 'Evaluation' above.)
•Beryllium lymphocyte proliferation test – A blood beryllium lymphocyte proliferation test (BeLPT) is the initial diagnostic test of choice for patients with clinical or radiographic evidence of lung disease and an occupational or environmental history of beryllium exposure. This test is also used to screen exposed workers for beryllium sensitization. (See 'Beryllium lymphocyte proliferation test' above.)
•Chest CT – A high-resolution computed tomographic (HRCT) scan is usually obtained to characterize the radiographic pattern and to identify the areas of greatest involvement for bronchoalveolar lavage (BAL) or potential biopsy. (See 'Chest imaging' above.)
•Bronchoalveolar lavage and bronchoscopic biopsy – For patients with a positive blood BeLPT or a strong clinical suspicion for CBD despite a negative blood BeLPT, the next test is usually fiberoptic bronchoscopy with BAL, endobronchial biopsy, and transbronchial biopsy. To obtain an adequate number of cells for BeLPT, a BAL volume of at least 240 mL of saline (in 4 aliquots of 60 mL) and up to 480 mL is obtained. In addition, BAL fluid is sent for cell and differential counts, and also microbiologic and cytologic analyses. (See 'Beryllium lymphocyte proliferation test' above.)
●Diagnostic criteria – The diagnosis of CBD requires all three of the following findings: a history of beryllium exposure, a positive BeLPT, and the presence of noncaseating granulomas and/or mononuclear cell infiltrates on lung histopathology. However, if biopsies are not available or are nondiagnostic, a clinical diagnosis can also be made based on a positive BAL BeLPT and lymphocytosis (>20 percent) in bronchoalveolar lavage fluid. (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis of CBD includes sarcoidosis, hypersensitivity pneumonitis, granulomatous vasculitides, mycobacterial infection, and other granulomatous lung diseases (eg, due to other metals like aluminum or titanium and drug-induced hypersensitivity). (See 'Differential diagnosis' above.)
●Beryllium avoidance, in sensitized patients – For patients who meet criteria for beryllium sensitization, but not CBD, cessation of exposure to beryllium is advised due to the risk of developing CBD if exposure continues. (See 'Supportive therapy' above.)
●Treatment
•Beryllium avoidance – All patients who meet criteria for CBD require cessation of exposure to beryllium. (See 'Avoidance of beryllium exposure' above.)
•Supportive therapy – Supportive care may include smoking cessation counselling, vaccination against pneumococcus and influenza, supplemental oxygen, and pulmonary rehabilitation, as indicated. (See 'Supportive therapy' above.)
•Monitoring and treatment of patients with mild disease – For those who have minimal to no symptoms and mild or no impairment in physiologic testing, we reassess symptoms and lung function at periodic intervals and initiate therapy in the event of disease progression. Some of these patients may benefit from a trial of inhaled glucocorticoids based on limited evidence from case reports. (See 'Asymptomatic or mild disease' above.)
•Immunosuppressant therapy for patients with more severe disease
-Initial treatment with systemic glucocorticoids – For patients with more bothersome cough or dyspnea, impaired baseline lung function (vital capacity, total lung capacity, or diffusing capacity that are below 70 percent of predicted), or a decline in lung function during observation (by more than 10 percent of predicted), we suggest treatment with systemic glucocorticoids rather than observation or inhaled glucocorticoids alone (Grade 2C).
Typically, we begin oral prednisone at 20 to 40 mg once daily. Tapering of prednisone is guided by the clinical response. Usually after six to eight weeks, prednisone is tapered to 15 to 20 mg daily (or an alternate day equivalent dose) and after several months to 5 to 10 mg daily (or an alternate day equivalent). (See 'Initial treatment with glucocorticoids' above.)
-Management of glucocorticoid-refractory disease – For patients who fail to respond to glucocorticoids or experience adverse effects from glucocorticoids, other immunosuppressive agents (eg, methotrexate, azathioprine, infliximab) may be tried, although clinical trials supporting this practice have not been published. (See 'General management' above.)
●Prognosis – CBD has a variable clinical course; published mortality rates range from 6 to 35 percent. (See 'Prognosis' above.)
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