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Chapter 64
Chronic Beryllium Disease Misdiagnosed
asSarcoidosis
AbdullaKhan andJoseLuisFerrero
Learning Objectives
By the end of this section, the clinician will be able to:
1. Discuss the presentation, pathologic progression, and nature of the disease.
2. Recognize the prevalence of misdiagnosed cases of CBD among the population.
3. Discuss and analyze the consequence and importance of timely diagnosis and its
effect on the prognosis of the disease.
4. Enumerate the diagnostic criteria and challenges in diagnosing a patient
with CBD.
5. Analyze up-to-date diagnostic techniques such as biomarkers and their
importance.
6. Delineate the diagnostic challenges and common errors that a physician might
encounter when evaluating a patient with CBD.
Introduction
Occupational respiratory disorders are work-related lung diseases that are caused by
long-term exposure to a variety of toxic particulates, hazardous chemicals, and
fumes. Berylliosis or chronic beryllium disease (CBD) is an occupational
A. Khan (*) · J. L. Ferrero
St. Martinus University Faculty of Medicine, Willemstad, Curacao
e-mail: abdulla.khan@martinus.edu; luis.ferrero@martinus.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
H. Tohid et al. (eds.), The Misdiagnosis Casebook in Clinical Medicine,
https://doi.org/10.1007/978-3-031-28296-6_64
473
474
A. Khan and J. L. Ferrero
hypersensitivity granulomatous disease caused by exposure to beryllium (Be) and is
characterized by the formation of noncaseating, non-necrotizing granulomas predominantly in the lungs and skin [1]. Be being an integral component is used in
many manufacturing industries such as metal and alloy, aerospace, ceramic, defense,
computer microchips, automotive industry, jewelry making, and dental laboratories,
thereby increasing the risk of exposure among the population [1, 2]. CBD is one of
the most commonly misdiagnosed occupation-related lung diseases and is present
in 2–5% of beryllium-exposed workers [1]. Misdiagnosis of CBD is attributable to
the varying clinical course (asymptomatic → severe respiratory failure) of the disease and the inconsistent onset of action (acute → 20years or more) [3]. It is most
commonly misdiagnosed as sarcoidosis (systemic granulomatous inammatory disease) because of its strong clinical and pathologic association with CBD followed
by idiopathic pulmonary brosis (IPF) and hypersensitivity pneumonitis [4]. Hence
a detailed occupational history and multidisciplinary approach are necessary for
formulating an accurate diagnosis. Here we present a case of a 27-year-old dental
technician who presented to the ER in respiratory distress and was initially misdiagnosed as having sarcoidosis and managed with IV corticosteroids [5]. Upon further investigation, a diagnosis of CBD was conrmed.
Clinical Case Presentation
The case reports of a 27-year-old female dental technician who presented to the ER
in severe respiratory distress. Sixmonths before admission, she presented with dyspnea, weakness, nausea/vomiting, and diarrhea and reported a weight loss of about
12kg. She was treated with Prozac as her medical history and chest X-ray ndings
were unexceptional. The initial study was unexceptional, and radiologic examination consisting of chest X-ray and computed tomography (CT) later revealed an
increased interstitial pattern in addition to hilar lymphadenopathy. Echocardiography
showed a signicant increase in pulmonary pressure (90mmHg), tricuspid valve
insufciency, and right atrial and ventricular enlargement. Blood work showed elevated hepatic enzymes; arterial blood gas (ABG) analysis reported pCO2=38.9,
pO2= 67, and pH = 7.358; and serologic examination was negative for all other
diseases that were tested for (HIV, hepatitis B, hepatitis C). Pulmonary function test
(PFT) was conducted reporting the following results (refer to Table64.1).
Pulmonary function results were suggestive of a restrictive lung disease pattern
with decreased diffusing capacity of the lung which required the use of high oxygen
ow. An open lung biopsy was performed, and the histopathological analysis
revealed the presence of abundant noncaseating granuloma, favoring the diagnosis
of sarcoidosis which was managed with intravenous hydrocortisone followed by
60mg of Meticorten (oral prednisone). The patient’s condition improved and the
mediastinal lymphadenopathy was resolved. Similar cases have been observed in
other dental technicians [6], which were conspicuous and demanded a re-evaluation
64 Chronic Beryllium Disease Misdiagnosed asSarcoidosis
Table 64.1 Pulmonary function test result
PFT parameter % Predicted
FEV1 48
FVC 44
FEV1/FVC 95
TLC 53
DLCO 24
DLCO/vacuum aspiration 46
FEV1, forced expiratory volume in 1s; FVC, forced vital capacity; FEV1/FVC, absolute ratio;
DLCO, diffusing capacity of the lungs for CO
475
because of the patient’s occupational history. Chemical analysis of the patient’s
sputum revealed abundant particles of clay minerals. Beryllium Lymphocyte
Transformation Test (BeLTT) showed a 5.90 and 2.54 index (normal <1.7) at
10-4M and 10-5M of BeSO4, respectively. A genetic study revealed that the patient
was homozygous for HLA-DPB1-Glu69, conrming the diagnosis of chronic beryllium disease.
Differential Diagnosis
1. Sarcoidosis—It is a multisystem noncaseating granulomatous inammatory dis-
ease of unknown etiology characterized by the formation of reticular opacities in
the lung and bilateral hilar lymphadenopathy. Biopsy of the affected lung tissue
and a negative reaction to BeLTT is helpful in distinguishing it from berylliosis.
2. Idiopathic pulmonary brosis—Lung disease of unknown etiology character-
ized by progressive brosis of the pulmonary interstitium leading to a decline in
pulmonary function. Peripheral distribution of bilateral brosis patterns on computed tomography differentiates it from CBD.
3. Hypersensitivity pneumonitis—It is a nonatopic, non-asthmatic inammatory
pulmonary disease characterized by prolonged exposure to antigen resulting in a
hypersensitivity reaction. A positive hypersensitivity pneumonitis antibody
panel is supportive in differentiating it from berylliosis.
4. Tuberculosis—It is an infectious disease caused by Mycobacterium tuberculosis
bacteria mainly affecting the lungs characterized by the formation of caseating
granuloma. Chest X-ray pattern for tuberculosis and a tuberculin skin test
(Mantoux test) help us to differentiate it from berylliosis.
5. Asthma—It is a chronic inammatory disease of the respiratory system charac-
terized by bronchial hypersensitivity followed by reversible airway obstruction
and narrowing of the airways. Pulmonary function test shows an obstructive lung
pattern rather than restrictive type which is found in patients with CBD.
476
A. Khan and J. L. Ferrero
Discussion
Berylliosis or chronic beryllium disease (CBD) is a noninfectious granulomatous
disease caused by the exposure to Be metal or its salts leading to symptoms such as
nonproductive cough, dyspnea on exertion, weight loss, chest pain, and fatigue.
CBD is a metal-induced delayed type IV hypersensitivity reaction characterized by
beryllium sensitization due to recurrent exposure (formation of specic CD4+
memory T cells). Memory CD4+ T cells are reactivated upon subsequent exposure
resulting in the release of multiple cytokines and chemokines causing the aggregation of T cells, macrophages, and plasma cells to form noncaseating granulomas and
pulmonary brosis [1, 7, 8]. Epigenetic factors such as age, sex, race, and ethnicity
also predispose to an increased susceptibility to pulmonary disease from beryllium
exposure [9]. Genetic susceptibility to BeS (beryllium sensitization) and CBD has
been found in many studies associated with polymorphism of the HLA-DP ß1 chain
gene [10]. The presence of a similar pathognomonic lesion (epithelioid granuloma)
and indistinguishable clinical manifestations in patients with both diseases makes it
challenging to distinguish CBD from sarcoidosis [11]. Sarcoidosis is a systemic
granulomatous inammatory disease [12] characterized by the formation of noncaseating granuloma with an incidence rate of 14.5 per 100,000 citizens in the United
States [13]. Remarkably, nearly 6% of the people diagnosed with sarcoidosis may
have CBD [1] similar to the clinical case presented. It is an exceptional case of misdiagnosis caused by the decient history taking that might have caused the delay in
diagnosis and management of the patient. A denitive diagnosis of CBD is established based on the patient’s occupational history and specic diagnostic criteria
and tests. The criteria are as follows: [7, 14]
1. Exclusion of all other known granulomatous diseases
2. A previous history of exposure, either direct or indirect contact (family members
exposed to Be, industrial accidents)
3. Histopathologic evidence of the presence of granuloma in the affected tissue
4. Evidence of immunological reactivity to Be via BeLTT (Beryllium Lymphocyte
Transformation Test)
5. Consistent clinical, radiographic (chest X-ray, HRCT), and physiologic fea-
tures of CBD
Another factor in the misdiagnosis of CBD is a low sensitivity (68.3%) of the
BeLTT despite its high specicity (96.9%) [10], which eventually warrants the use
of other noninvasive, accurate diagnostic tools such as the use of genomic biomarkers. The ongoing gene expression studies have found that expression of IFN-γ
(interferon gamma), CD55 (cluster of differentiation 55/complement decay accelerating factor), RNase 3 (ribonuclease 3), TNF-α (tumor necrosis factor alpha), and
CXCL9 (chemokine {C-X-C motif} ligand 9) are some biomarkers that can be used
to distinguish between CBD and sarcoidosis. In CBD, the biomarkers CD55 and
TNF-α were overexpressed, and CXCL9 was under-expressed [10, 15]. The diagnosis of CBD is further complicated by the lack of certied testing centers across the
64 Chronic Beryllium Disease Misdiagnosed asSarcoidosis
477
United States that detects beryllium sensitization and the eventual development of a
multisystemic disease suggesting a diagnosis of sarcoidosis rather than
CBD.Therefore, a fastidious evaluation of the patient history and clinical manifestation is necessary to avoid misdiagnosis of CBD.
Management goals of CBD focus on improving patient survival by decreasing
the progression of the disease and improving the symptoms. Apart from organ transplantation, no cure has been found yet to manage CBD. Corticosteroids are gold
standard in the treatment of CBD.The use of inhaled corticosteroids has given evidence of stabilizing the decline in pulmonary function and shown improvements in
symptoms (cough) [16]. Most cases require lifelong follow-up with chest X-ray,
physical exams, and PFTs. Oxygen supplementation, vaccination, pulmonary rehabilitation, and lifestyle changes with exercise and diet are supportive in managing
the patient with CBD.Prevention can be attained by reducing exposure with the
help of a respirator (protective mask) and replacing the material with much
safer ones.
Conclusion
Chronic beryllium disease misdiagnosis is not an infrequent nding among patients
diagnosed with sarcoidosis. Clinicians must conduct a thorough physical examination and a meticulous assessment of the patient’s history (occupational background)
since it is critical to avoid misdiagnosis of CBD.Hence continuous medical surveillance and frequent inspection by the respective authorities are necessary to keep the
incidence of disease under check.
References
1. Sizar O, Talati R.Berylliosis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022.
2. Tarlo S. Occupational lung disease Goldman’s Cecil medicine. 2012;567–74. https://doi.
org/10.1016/B978- 1- 4377- 1604- 7.00093- 2
3. Franquet T, Franks TJ, Galvin JR, etal. Non-infectious granulomatous lung disease: imaging ndings with pathologic correlation. Korean J Radiol. 2021;22(8):1416–35. https://doi.
org/10.3348/kjr.2020.1082.
4. Ohshimo S, Guzman J, Costabel U, Bonella F.Differential diagnosis of granulomatous lung
disease: clues and pitfalls: Number 4in the Series “Pathology for the clinician” Edited by Peter
Dorfmüller and Alberto Cavazza. Eur Respir Rev. 2017;26(145):170012. Published 2017 Aug
9. https://doi.org/10.1183/16000617.0012- 2017.
5. Fireman E, Kramer MR, Kaufman N, Müller-Quernheim J, Lerman Y.Beryllium disease: rst
case reported in Israel. Isr Med Assoc J. 2001;3(3):224–5.
6. Fireman E, Kramer MR, Priel I, Lerman Y.Chronic beryllium disease among dental technicians in Israel. Sarcoidosis Vasc Diffuse Lung Dis. 2006;23(3):215–21.
7. Balmes JR, Abraham JL, Dweik RA, etal. An ofcial American Thoracic Society statement:
diagnosis and management of beryllium sensitivity and chronic beryllium disease. Am J
Respir Crit Care Med. 2014;190(10):e34–59. https://doi.org/10.1164/rccm.201409- 1722ST.
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8. Fontenot AP.Immunologic effects of beryllium exposure. Ann Am Thorac Soc. 2018;15(Suppl
2):S81–5. https://doi.org/10.1513/AnnalsATS.201707- 573MG.
9. Vlahovich KP, Sood A.A 2019 update on occupational lung diseases: a narrative review. Pulm
Ther. 2021;7:75–87.
10. Lin NW, Maier LA, Mroz MM, etal. Genomic biomarkers in chronic beryllium disease and
sarcoidosis. Respir Med. 2021;187:106390. https://doi.org/10.1016/j.rmed.2021.106390.
11. Mayer AS, Hamzeh N, Maier LA. Sarcoidosis and chronic beryllium disease: similarities and differences. Semin Respir Crit Care Med. 2014;35(3):316–29. https://doi.
org/10.1055/s- 0034- 1377059.
12. Bokhari SRA, Zulqar H, Mansur A. Sarcoidosis. In: StatPearls. Treasure Island (FL):
StatPearls Publishing; 2022.
13. Sikjær MG, Hilberg O, Ibsen R, Løkke A.Sarcoidosis: a nationwide registry-based study of
incidence, prevalence and diagnostic work-up. Respir Med. 2021;187:106548. https://doi.
org/10.1016/j.rmed.2021.106548.
14. Müller-Quernheim J, Gaede KI, Fireman E, Zissel G.Diagnoses of chronic beryllium disease
within cohorts of sarcoidosis patients. Eur Respir J. 2006;27(6):1190–5. https://doi.org/10.118
3/09031936.06.00112205.
15. Kraaijvanger R, Janssen Bonás M, Vorselaars ADM, Veltkamp M.Biomarkers in the diagnosis
and prognosis of sarcoidosis: current use and future prospects. Front Immunol. 2020;11:1443.
https://doi.org/10.3389/mmu.2020.01443.
16. Mroz MM, Ferguson JH, Faino AV, Mayer A, Strand M, Maier LA.Effect of inhaled corticosteroids on lung function in chronic beryllium disease. Respir Med. 2018;138S:S14–9. https://
doi.org/10.1016/j.rmed.2018.01.009.
A. Khan and J. L. Ferrero
Chapter 65
Idiopathic Pulmonary Fibrosis
Misdiagnosed asSputum-Negative
Tuberculosis
AbdullaKhan andJoseLuisFerrero
Learning Objectives
By the end of this section, the clinician will be able to:
1. Review the presentation, pathologic progression, and nature of the disease.
2. Recognize the prevalence of misdiagnosed cases of IPF and understand the
importance of a multidisciplinary care team in the management of the disease.
3. Discuss and analyze the importance of a timely diagnosis and its effect on the
prognosis of the disease.
4. Discuss and enumerate the international guidelines and diagnostic algorithm in
diagnosing a patient with IPF.
5. Explain the up-to-date diagnostic techniques such as biomarkers and their
importance in the denitive diagnosis of IPF.
6. Delineate the diagnostic challenges and common errors that a physician might
encounter when evaluating a patient with idiopathic pulmonary brosis.
Introduction
Interstitial lung diseases (ILDs) conform a group of restrictive respiratory disorders
affecting the interstitial areas of the lung, which support the alveolar epithelium,
such as the basement membrane, pulmonary capillary endothelium, and
A. Khan (*) ·J. L. Ferrero
St. Martinus University Faculty of Medicine, Willemstad, Curacao
e-mail: abdulla.khan@martinus.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
H. Tohid et al. (eds.), The Misdiagnosis Casebook in Clinical Medicine,
https://doi.org/10.1007/978-3-031-28296-6_65
479
480
A. Khan and J. L. Ferrero
perivascular and perilymphatic tissues. In most cases, it is due to an abnormality in
structural remodeling after an injury leading to brosis and scarring of the lung tissue [1]. The injury could be due to exposure to chemicals (chemotherapy, medications), occupational/environmental (organic/inorganic fumes, toxic dust, radiation),
or due to an underlying autoimmune disease (rheumatoid arthritis, systemic lupus
erythematosus, scleroderma) or due to an unknown etiology. Idiopathic pulmonary
brosis (IPF) is an ILD with an unknown underlying cause characterized by progressive brosis of the pulmonary interstitium and persistent decline in pulmonary
function leading to respiratory failure. It is one of the common forms of ILD, usually presented either in the fth or sixth decade of life, with a global incidence at an
estimated rate of 2.8–9.3 per 100,000 per year in North America and Europe [2].
Regardless of the numerous advancements in medicine, diagnosis and management of IPF persists as a signicant challenge even to experienced clinicians, due to
the indistinguishable nature of the disease, poor prognosis, and high mortality rate
with a reported mean survival age of only 2–3years [2]. Hence diagnosis and management of IPF require a quick, multidisciplinary approach to minimize diagnostic uncertainty. Awareness of these conditions must be the norm for nonspecialized members
of the health-care team and not only for practitioners with a specialization.
Here we report a case of a 55-year-old patient who was initially misdiagnosed
with negative sputum tuberculosis and treated with antitubercular drug regimen
without any favorable outcome [3]. Studies have shown that more than 50% of the
patients with IPF are initially misdiagnosed [2], with other respiratory illnesses
such as bronchitis, pneumonia, tuberculosis, asthma, chronic obstructive pulmonary
disease (COPD), and emphysema, which also account for the diagnostic delay,
hence the poor prognosis of the disease.
Clinical Case Presentation
The case reports of a 55-year-old male textile trader who presented to the clinic with
the chief complaint of breathlessness for 3years and dry cough for the past 2.5years.
The patient was diagnosed with tuberculosis 2 months prior to the presentation and
reported to have started treatment with antituberculosis medication with no signicant symptomatic relief. General physical examination was unremarkable and vital
signs were stable with SPO2 of 96% on room air. Comprehensive systemic examinations were normal except for signicant end-inspiratory bi-basal velcro-like crackles on thoracic examination. Chest X-ray shows streaky and patchy opacities in the
lower zone bilaterally, and computed tomography (CT) of the lung revealed extensive nodular opacities/ground-glass appearance with honeycombing of the soft tissue of the entire lung eld.
Pulmonary function test (PFT) was performed which showed a restrictive lung
pattern with the following results (refer to Table65.1):
65 Idiopathic Pulmonary Fibrosis Misdiagnosed asSputum-Negative Tuberculosis
Table 65.1 Pulmonary function test result
PFT parameter Predicted Value % Predicted
FEV1 3.21 2.63 81.93%
FVC 3.92 2.64 67.34%
FEV1/FVC 79.11 99.77 126.11%
FEV1, forced expiratory volume in 1s; FVC, forced vital capacity; FEV1/FVC, absolute ratio
481
Histopathologic examination of the lung tissue through lung tissue biopsy
revealed moderate lymphocytic inltration of the lung parenchyma with associated
patchy interstitial brosis and adjacent areas of normal tissue.
After a complete evaluation, the patient was diagnosed with idiopathic pulmonary brosis (IPF). Management was initiated on tablet prednisolone 1mg/kg daily,
tablet rabeprazole 40mg 12 hourly, and supplements for bone health.
Differential Diagnosis
1. Chronic hypersensitivity pneumonitis (CHP) —Hypersensitivity pneumonitis is
a nonatopic, non-asthmatic inammatory pulmonary disease caused by prolonged repetitive inhalation of antigens from the environment. Although both the
diseases have similar radiologic and histopathologic presentation, presence of
features such as bridging brosis, lymphoid aggregation, and intraluminal brosis can be helpful in differentiating CHP from IPF.
2. Asbestosis—It is an interstitial lung disease caused by inhalation of asbestos
bers predominantly seen in people who work in close contact with asbestos.
The bers cause inammation followed by brosis and scar formation. The
brosis appears coarser in CT ndings, and presence of asbestos bodies differentiates it from IPF.
3. Desquamative interstitial pneumonia—It is characterized by extensive alveolar
inltration of macrophages followed by interstitial inammation and brosis. It
is predominantly found among cigarette smokers (90% cases) during the fourth
or fth decade of life. Smoking cessation and avoidance of second-hand smoking are essential for better prognosis of the disease.
4. Drug-induced pulmonary brosis—Cytotoxic drugs such as bleomycin and
noncytotoxic drugs such as amiodarone are commonly found to induce pulmonary brosis. Proper history taking is necessary in order to rule out the
differential.
5. Respiratory bronchiolitis interstitial lung disease—A mild inammatory pul-
monary disorder prevalent invariably among former heavy smokers/current
smokers. It is characterized by accumulation of yellow-brown pigmented macrophages within the lumen of respiratory bronchioles associated with submucosal and peribronchiolar inammation, which can be used to differentiate it
from IPF.
482
A. Khan and J. L. Ferrero
Discussion
Idiopathic pulmonary brosis (IPF) is one of the most lethal diseases among other
ILDs, which may further progress into respiratory failure due to cumulative brosis
and destruction of the lung architecture. Although the exact etiology of IPF is still
unknown, exposure to tobacco smoke, environmental pollutants, chronic aspiration
due to GERD (gastroesophageal reux disease), and medications (bleomycin,
cyclophosphamide, nitrofurantoin) are some of the prevalent risk factors [4].
The case mentioned here described a patient diagnosed with sputum-negative
tuberculosis due to nonspecic clinical manifestation and who was started on antitubercular drug regimen without any signicant relief [3]. The case is prototypical
of misdiagnosis as the initial diagnosis was made on the disease prevalence and its
clinical correlation with IPF. According to studies conducted, patients diagnosed
with IPF possess ve times increased risk for incidence of tuberculosis than the
general population [5]. Furthermore, patients in TB-endemic areas usually undergo
empirical antitubercular treatment even if the sputum/smear test is negative for
Mycobacterium tuberculosis which may further lead to diagnostic delay and
accounts for the poor prognosis of the disease [6].
Genetic predisposition (Fig.65.1) can also be established in some familial cases
of pulmonary brosis based on mutations in the telomerase genes (e.g., TERT),
surfactant genes (e.g., SFTPA2), mucin genes (e.g., MUC5B), and surfactant proteins SPC and SPA [7]. Therefore, a meticulous evaluation of the patient history is
a prerequisite for the correct and complete diagnosis of IPF.
Diagnosis of IPF is quite challenging which is attributable to the complexity of
the disease and the presentation of nonspecic symptoms that could misdirect to the
Fig. 65.1 Genetic predisposition among patients with idiopathic pulmonary brosis