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Arcana, R.I.;  Crișan-Dabija, R.;  Cernomaz, A.T.;  Buculei, I.;  Burlacu, A.;  Zabară, M.L.;  Trofor, A.C. Key Elements in Diagnosing Pulmonary Sarcoidosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/40318 (accessed on 05 December 2025).
Arcana RI,  Crișan-Dabija R,  Cernomaz AT,  Buculei I,  Burlacu A,  Zabară ML, et al. Key Elements in Diagnosing Pulmonary Sarcoidosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/40318. Accessed December 05, 2025.
Arcana, Raluca Ioana, Radu Crișan-Dabija, Andrei Tudor Cernomaz, Ioana Buculei, Alexandru Burlacu, Mihai Lucian Zabară, Antigona Carmen Trofor. "Key Elements in Diagnosing Pulmonary Sarcoidosis" Encyclopedia, https://encyclopedia.pub/entry/40318 (accessed December 05, 2025).
Arcana, R.I.,  Crișan-Dabija, R.,  Cernomaz, A.T.,  Buculei, I.,  Burlacu, A.,  Zabară, M.L., & Trofor, A.C. (2023, January 18). Key Elements in Diagnosing Pulmonary Sarcoidosis. In Encyclopedia. https://encyclopedia.pub/entry/40318
Arcana, Raluca Ioana, et al. "Key Elements in Diagnosing Pulmonary Sarcoidosis." Encyclopedia. Web. 18 January, 2023.
Key Elements in Diagnosing Pulmonary Sarcoidosis
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11010175

Sarcoidosis is a complex multisystemic granulomatous disease, with unknown etiology and variable clinical manifestations, which frequently manifests with thoracic (bilateral hilar lymphadenopathies and pulmonary infiltrates), ocular, and cutaneous involvement. The diagnosis of sarcoidosis requires the identification of noncaseated epithelioid granulomas in one or more organs along with the exclusion of other pathologies that could cause granulomatous lesions. 

sarcoidosis Biomarkers diagnosis

1. Introduction

Often, in clinical practice, the heterogeneity of the disease can lead to an erroneous diagnosis of sarcoidosis, often with a significant impact on the patient’s life. In the following, the researchers propose to highlight a series of investigations that can help establish a diagnosis as well as the diagnostic errors that may occur.
In regards to the symptoms, sarcoidosis can present itself in multiple forms and in various combinations, from asymptomatic or clinically insidious forms to acute forms with multiple organ involvement [1]. The most frequently affected organ is the lung, with a proportion of up to 90% [2], but the respiratory symptomatology remains in most cases poor, so regardless of the context, other signs and symptoms of the other organs must be looked for. In the table below (Table 1), the researchers show some of the most common signs and symptoms that can occur in sarcoidosis:
Table 1. Organ involvement and symptoms of sarcoidosis [2][3][4][5][6][7].

General Symptoms

Fever, Weight Loss, Fatigue, Concentration Disturbances, Night Sweats

Thoracic manifestations

Over 90% of cases

Cough, chronic dyspnoea, chest pain, wheezing

Bilateral hilar/mediastinal lymphadenopathy

Pulmonary infiltrates

Ocular involvement

10–25% of cases

Anterior or posterior uveitis, conjunctivitis, sicca syndrome, scleritis, episcleritis

Skin lesions

Up to 1/3 of the cases

Erythema nodosum, lupus pernio, granuloma development on scars

Cardiac involvement

1–23% of cases

Can be clinically occult or

Chest pain, palpitations, dyspnoea, syncope

Arrythmias—total heart block, tachyarrhythmias, cardiac failure

Musculoskeletal involvement

5–15% of cases for joint involvement

Sarcoid arthropathy, sarcoid myopathy, chronic sarcoid arthritis

Renal involvement

Up to 20% of cases

Granulomatous interstitial nephritis, nephrocalcinosis, nephrolithiasis

Neurologic involvement

3–10% of cases

Involvement of the cranial nerves: II, VII, VIII

Central nervous system or peripheral nervous system involvement

Meningeal irritation

Symmetrical mono/polyneuropathies, polyradiculopathy

Affecting the pituitary gland—diabetes insipidus, amenorrhea, galactorrhea

Otolaryngological involvement

5–15% of cases

Sinonasal involvement—nasal obstruction, rhinitis, epistaxis, rhinorrhea, anosmia

Laryngeal sarcoidosis—hoarseness, dysphagia, inspiratory dyspnoea

Löfgren Syndrome

Acute onset with fever, bilateral gilar lymphadenopathy, erythema nodosum, joint involvement

Heerfordt Syndrome

Fever, enlargement of the salivary/parotid glands, facial nerve paralysis, anterior uveitis
Considering the extremely varied clinical appearance that can lead to confusion and misdiagnosis, the patient suspected of sarcoidosis requires a rigorous evaluation from an anamnestic, clinical, biological, radiological, and histological point of view, often requiring interdisciplinary collaboration between a pulmonologist, cardiologist, dermatologist, ophthalmologist, and neurologist. It is wrong to base the diagnosis on the mere association of some clinical symptoms. A thorough anamnesis is important, as it can identify exposures to respiratory toxins in the work environment (silica dust, beryllium) or exposures to various substances or antigens that could cause interstitial lung disease [1]. Highlighting a positive epidemiological context for tuberculosis in the family or in close contact, even in the past, may point the diagnosis toward tuberculosis.

2. Biomarkers in Sarcoidosis

Laboratory tests are an integral part of the diagnostic process of suspected sarcoidosis. Although there are no standardized or definitive biological markers, a series of tests can guide the diagnosis (Table 2).
Table 2. Serum biomarkers in sarcoidosis [1][8][9][10][11][12].

Serum angiotensin convertase—ACE

  • Enzyme produced by epithelioid cells derived from activated macrophages from the site of the granuloma

  • Increased values in the serum of patients with sarcoidosis, especially in active forms

  • A normal value does not necessarily exclude sarcoidosis

  • ACE can also be found increased in other granulomatous diseases, such as tuberculosis and pneumoconiosis

  • Remains poorly specific and sensitive for the diagnosis of sarcoidosis

Serum soluble Interleukin 2 receptor—sIL-2R

  • Marker of Th1 cell activation in relation to the evolution of the granuloma

  • Elevated levels of sIL-2R have been described in active sarcoidosis and multiple organ involvement

  • There are a number of other diseases in which sIL-2R can be elevated, such as other granulomatous diseases, infections, lymphoproliferative diseases, and autoimmune disorders

Cytokines (IL-18, IL-12), neopterin, lysozyme, serum amyloid A

  • Often useful in patients for monitoring the evolution of the disease, less for diagnosis because they do not have a high enough accuracy

  • Most of the time, these biomarkers are difficult and expensive to use in a clinical setting
ACE levels in patients suspected of sarcoidosis can also be influenced by genetic variations and ACE inhibitor therapy. One study by d’Alessandro et al., who analyzed serum samples from patients diagnosed with sarcoidosis and taking ACE inhibitor therapy, found that serum ACE levels were lower in these patients compared to those not taking ACEIs [13].

3. Imagistic Investigation in Pulmonary Sarcoidosis

Chest radiography has long been, and still is, a key investigation in the diagnosis of sarcoidosis. The Scadding classification made in 1961 divided sarcoidosis into five stages (Table 3) [1]. This classification is still used today, but the accuracy based on radiological presentation is only 50% [14]
Table 3. Radiological classification of pulmonary sarcoidosis [1].

Stage of Disease

Radiological Findings

Stage 0 disease

Normal Findings on Chest Radiography

Stage 1 disease

Bilateral hilar/mediastinal lymphadenopathy

Stage 2 disease

Bilateral hilar/mediastinal lymphadenopathy and pulmonary infiltrates

Stage 3 disease

Pulmonary infiltrates without hilar lymphadenopathy

Stage 4 disease

Pulmonary fibrosis
On the other hand, the use of HRCT (high-resolution computer tomography) examination can detect abnormalities unidentifiable on a simple chest X-ray, including micronodules or pleural involvement, and can more accurately examine lung parenchyma, lung hilum, and mediastinal lymph node stations [14]. Considering the fact that chest HRCT examination is clearly superior to chest X-ray, it is useful to recommend and perform in the suite of investigations necessary to establish the diagnosis (Table 4).
Table 4. HRCT aspects that can be encountered in sarcoidosis [15][16][17][18].

The Predominance of Lesions in the Middle and Upper Lung Regions

Suggestive of Sarcoidosis

Perilymphatic micronodules between 1–5 mm, most frequently located subpleural, along the interlobular septae or interlobar fissures, respectively, of the bronchovascular bundles

Suggestive of sarcoidosis

The galaxy sign (central dominant nodule surrounded by numerous satellite micronodules)

Lends itself to diagnostic confusion with malignant lung disease

Miliary pattern

Very rare cases

Symmetrical, bilateral adenopathies

Mediastinal and hilar lymph node involvement—frequently right lower paratracheal, right hilar, subcarinal, subaortic, interlobar stations

Isolated mediastinal adenopathy—atypical

Fibrotic changes

Distortions of the normal lung parenchyma architecture, with reticular thickening, bronchiectasis and traction bronchiole ectasis, respectively, and loss of lung volume

Atypical patterns

Cavitary lesions, solid lesions surrounded by ground-glass opacities known as the halo sign or atoll sign—ground-glass opacity surrounded by a denser consolidation and pleural effusions
One interesting imaging technique that can be useful in the diagnosis of sarcoidosis is 18 fluorodeoxyglucose (FDG) PET/CT. In thoracic sarcoidosis, mediastinal and hilar lymphadenopathy is found to be hypermetabolic on FDG PET/CT, as well as other parenchymal lesions such as nodules or masses. Although it is not recommended as a part of the initial workup, FDG PET/CT can provide essential information regarding the extent of the disease, cardiac and bone involvement, and the response to treatment, and can also guide a convenient biopsy site [19].

4. Fiberbronchoscopic Examination and Bronchoalveolar Lavage

Fiberbronchoscopic examination and bronchoalveolar lavage represent an integral part of the diagnosis of sarcoidosis and should be performed in every eligible patient who has no absolute contraindications.
Although in most cases the macroscopic endobronchial appearance is normal, the presence of granulations of the bronchial mucosa, secondary to granulomatous inflammation, erythema of the mucosa, and a cobblestone appearance, have been cited [3][20].
Bronchoalveolar lavage cytology is sometimes used as a biological marker for sarcoidosis, but its exact role is not yet clarified. Although lymphocytosis and normal neutrophil and eosinophil levels are frequent in the lavage of sarcoidosis patients, the diagnostic value of such findings is under debate; a similar situation is reported for CD4/D8 ratio [21]. Bronchoalveolar lavage cytology may reveal a moderate increase in the total number of cells, with lymphocytosis values between 30–50%. Although the evidence of increased neutrophils is rare in sarcoidosis, in cases with advanced pulmonary fibrosis, neutrophilia in the lavage can be identified. The CD4/CD8 ratio is frequently increased, and the cutoff used is a ratio value above 3.5. However, these values are more frequently found in the active stage of the disease. Normal CD4/CD8 ratio values do not exclude sarcoidosis, as the disease may be inactive at the time of examination [8].
On the other hand, lymphocytosis is not specific to sarcoidosis, being found in many other diseases such as tuberculosis or pulmonary mycosis, especially in the context of a CD4/CD8 ratio below 3.5 [22].
The advantage of the fiberbronchoscopic examination is the performance of biopsies using the different techniques illustrated, alone or combined (Table 5). The diagnostic yield is higher the more biopsy techniques are used [22]:
Table 5. Diagnostic biopsy yield in different fiberbronchoscopic techniques [22].

Method of Biopsy

Diagnostic Yield

Endobronchial biopsy (EBB)

Variable between 20–61%

Higher accuracy when endobronchial abnormal appearances are present

Transbronchial lung biopsy (TBB)

Variable detection rate between 12–66% for Stage 1 disease

Conventional transbronchial needle aspiration (c-TBNA)

Variable depending on the lymph node sampling, between 6–90% diagnostic accuracy

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS—TBNA)

Variable between 80–94%

Transbronchial lung cryobiopsy (TBLC)

Variable between 74–98%, pooled estimate at 80%

5. Histopathological Findings

The typical histological pattern is epithelioid granuloma with a compact agglomeration of epithelioid cells and multinucleated histiocytes, with rare lymphocytes, non-necrotizing. In rare cases, granulomas with caseification can also be found. However, highlighting the granuloma without caseification does not establish the diagnosis of sarcoidosis, as it is necessary to integrate clinical–radiological and serological investigations to form a complete picture, in order to attain a diagnosis of increased accuracy [1][5][22].
Even if the disease in question is pulmonary sarcoidosis, radioclinical manifestations are not sufficient for an accurate diagnosis, and obtaining biopsies from mediastinal/hilar lymphadenopathies or from the lesions expressed in lung parenchyma should represent a priority for the clinician to avoid a false diagnosis of sarcoidosis [22]. If obtaining material for the histopathological examination cannot be achieved through fiber bronchoscopy, mediastinoscopy or video-assisted lung biopsy may be indicated procedures if the patient does not have major contraindications [23].
Whenever possible, other organs should be investigated where a less invasive biopsy sample could be obtained, such as a skin lesion or a conjunctival nodule (with the exception of erythema nodosum lesions) [23].
The only form of sarcoidosis considered specific enough to not require a biopsy is Lofgren’s syndrome with the association of bilateral hilar adenopathy, erythema nodosum, fever and joint involvement, lupus pernio and Heerfordt syndrome [5][23].

References

  1. Govender, P.; Berman, J.S. The Diagnosis of Sarcoidosis. Clin. Chest Med. 2015, 36, 585–602.
  2. Yee, A.M.F. Sarcoidosis: Rheumatology Perspective. Best Pract. Res. Clin. Rheumatol. 2016, 30, 334–356.
  3. Tana, C.; Donatiello, I.; Caputo, A.; Tana, M.; Naccarelli, T.; Mantini, C.; Ricci, F.; Ticinesi, A.; Meschi, T.; Cipollone, F.; et al. Clinical Features, Histopathology and Differential Diagnosis of Sarcoidosis. Cells 2021, 11, 59.
  4. Fraga, R.C.; Kakizaki, P.; Valente, N.Y.S.; Portocarrero, L.K.L.; Teixeira, M.F.S.; Senise, P.F. Do You Know This Syndrome? Heerfordt-Waldenström Syndrome. An. Bras. Dermatol. 2017, 92, 571–572.
  5. Sève, P.; Pacheco, Y.; Durupt, F.; Jamilloux, Y.; Gerfaud-Valentin, M.; Isaac, S.; Boussel, L.; Calender, A.; Androdias, G.; Valeyre, D.; et al. Sarcoidosis: A Clinical Overview from Symptoms to Diagnosis. Cells 2021, 10, 766.
  6. Ungprasert, P.; Ryu, J.H.; Matteson, E.L. Clinical Manifestations, Diagnosis, and Treatment of Sarcoidosis. Mayo Clin. Proc. Innov. Qual. Outcomes 2019, 3, 358–375.
  7. Cereceda-Monteoliva, N.; Rouhani, M.J.; Maughan, E.F.; Rotman, A.; Orban, N.; Al Yaghchi, C.; Sandhu, G. Sarcoidosis of the Ear, Nose and Throat: A Review of the Literature. Clin. Otolaryngol. 2021, 46, 935–940.
  8. Jeny, F.; Bernaudin, J.-F.; Cohen Aubart, F.; Brillet, P.-Y.; Bouvry, D.; Nunes, H.; Valeyre, D. Diagnosis Issues in Sarcoidosis. Respir. Med. Res. 2020, 77, 37–45.
  9. Kahkouee, S.; Samadi, K.; Alai, A.; Abedini, A.; Rezaiian, L. Serum ACE Level in Sarcoidosis Patients with Typical and Atypical HRCT Manifestation. Pol. J. Radiol. 2016, 81, 458–461.
  10. Ramos-Casals, M.; Retamozo, S.; Sisó-Almirall, A.; Pérez-Alvarez, R.; Pallarés, L.; Brito-Zerón, P. Clinically-Useful Serum Biomarkers for Diagnosis and Prognosis of Sarcoidosis. Expert Rev. Clin. Immunol. 2019, 15, 391–405.
  11. Ganeshan, D.; Menias, C.O.; Lubner, M.G.; Pickhardt, P.J.; Sandrasegaran, K.; Bhalla, S. Sarcoidosis from Head to Toe: What the Radiologist Needs to Know. RadioGraphics 2018, 38, 1180–1200.
  12. Kraaijvanger, R.; Janssen Bonás, M.; Vorselaars, A.D.M.; Veltkamp, M. Biomarkers in the Diagnosis and Prognosis of Sarcoidosis: Current Use and Future Prospects. Front. Immunol. 2020, 11, 1443.
  13. d’Alessandro, M.; Bergantini, L.; Perrone, A.; Cameli, P.; Cameli, M.; Prasse, A.; Plataroti, D.; Sestini, P.; Bargagli, E. Serial Investigation of Angiotensin-Converting Enzyme in Sarcoidosis Patients Treated with Angiotensin-Converting Enzyme Inhibitor. Eur. J. Intern. Med. 2020, 78, 58–62.
  14. Zhang, Y.; Du, S.; Zhao, M.; Li, Q.; Zhou, Y.; Song, J.; Chen, T.; Shi, J.; Jie, B.; Li, W.; et al. Chest High-Resolution Computed Tomography Can Make Higher Accurate Stages for Thoracic Sarcoidosis than X-Ray. BMC Pulm. Med. 2022, 22, 146.
  15. Chopra, A.; Kalkanis, A.; Judson, M.A. Biomarkers in Sarcoidosis. Expert Rev. Clin. Immunol. 2016, 12, 1191–1208.
  16. Jameson, A.; Revels, J.; Wang, L.L.; Wang, D.T.; Wang, S.S. Sarcoidosis, the Master Mimicker. Curr. Probl. Diagn. Radiol. 2022, 51, 60–72.
  17. Calandriello, L.; D’Abronzo, R.; Pasciuto, G.; Cicchetti, G.; del Ciello, A.; Farchione, A.; Strappa, C.; Manfredi, R.; Larici, A.R. Novelties in Imaging of Thoracic Sarcoidosis. JCM 2021, 10, 2222.
  18. Shaikh, F.; Abtin, F.G.; Lau, R.; Saggar, R.; Belperio, J.A.; Lynch, J.P. Radiographic and Histopathologic Features in Sarcoidosis: A Pictorial Display. Semin. Respir. Crit. Care Med. 2020, 41, 758–784.
  19. Akaike, G.; Itani, M.; Shah, H.; Ahuja, J.; Yilmaz Gunes, B.; Assaker, R.; Behnia, F. PET/CT in the Diagnosis and Workup of Sarcoidosis: Focus on Atypical Manifestations. RadioGraphics 2018, 38, 1536–1549.
  20. Strâmbu, I.; Tudorache, V.; Belaconi, I.; Burlacu, O.; Danteș, E.; Fildan, A.E.; Mlădinescu-Fira, O.; Ioniță, D.; Mureșan, A.; Nicodin, A.; et al. Ghid de Diagnostic și Tratament al Pneumopatiilor Interstițiale Difuze; Societatea Română de Pneumologie Grupul de Lucru pentru Pneumopatii Interstițiale Difuze și Sarcoidoză: București, Romania, 2015; pp. 76–82, 83–85. ISBN 978-973-0-20120-8.
  21. Davidson, K.R.; Ha, D.M.; Schwarz, M.I.; Chan, E.D. Bronchoalveolar Lavage as a Diagnostic Procedure: A Review of Known Cellular and Molecular Findings in Various Lung Diseases. J. Thorac. Dis. 2020, 12, 4991–5019.
  22. Benzaquen, S.; Aragaki-Nakahodo, A.A. Bronchoscopic Modalities to Diagnose Sarcoidosis. Curr. Opin. Pulm. Med. 2017, 23, 433–438.
  23. Chopra, A.; Avadhani, V.; Tiwari, A.; Riemer, E.C.; Sica, G.; Judson, M.A. Granulomatous Lung Disease: Clinical Aspects. Expert Rev. Respir. Med. 2020, 14, 1045–1063.
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Subjects: Respiratory System
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Raluca Ioana Arcana
, Radu Crișan-Dabija , Andrei Tudor Cernomaz , Ioana Buculei , Alexandru Burlacu ,
Mihai Lucian Zabară
, Antigona Carmen Trofor
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Revisions: 2 times (View History)
Update Date: 18 Jan 2023
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