Key Elements in Diagnosing Pulmonary Sarcoidosis

Key Elements in Diagnosing Pulmonary Sarcoidosis: Comparison

Please note this is a comparison between Version 1 by Radu CRIȘAN-DABIJA and Version 2 by Peter Tang.

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, thwe 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][5]. The most frequently affected organ is the lung, with a proportion of up to 90% ^[2][6], 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), thwe researchers shshow 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]}.

Organ involvement and symptoms of sarcoidosis [6,7,8,9,10,11].

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

Table 2. Serum biomarkers in sarcoidosis ^{[1][8][9][10][11][12]}.

Serum biomarkers in sarcoidosis [1,5,12,13,14,15].

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
Thoracic manifestations Over 90% of cases	Cough, chronic dyspnoea, chest pain, wheezing Bilateral hilar/mediastinal lymphadenopathy Pulmonary infiltrates
Ocular involvement 10–25% of cases

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][16].

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][5]. This classification is still used today, but the accuracy based on radiological presentation is only 50% ^[14][17]

Table 3. Radiological classification of pulmonary sarcoidosis ^[1].

Radiological classification of pulmonary sarcoidosis [5].

Stage of Disease	Radiological Findings

^{][16][17][18]}.

HRCT aspects that can be encountered in sarcoidosis [18,19,20,21].

The Predominance of Lesions in the Middle and Upper Lung Regions	Suggestive of Sarcoidosis

^22][25]:

Table 5. Diagnostic biopsy yield in different fiberbronchoscopic techniques ^[22].

Diagnostic biopsy yield in different fiberbronchoscopic techniques [25].

Method of Biopsy	Diagnostic Yield
Stage 0 disease	Normal Findings on Chest Radiography
Stage 1 disease
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
Endobronchial biopsy (EBB)	Variable between 20–61% Higher accuracy when endobronchial abnormal appearances are present
Anterior or posterior uveitis, conjunctivitis, sicca syndrome, scleritis, episcleritis
Bilateral hilar/mediastinal lymphadenopathy
The galaxy sign (central dominant nodule surrounded by numerous satellite micronodules)	Lends itself to diagnostic confusion with malignant lung disease	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
Stage 2 disease
Miliary pattern	Bilateral hilar/mediastinal lymphadenopathy and pulmonary infiltrates
	Very rare cases	Stage 3 disease
Symmetrical, bilateral adenopathies	Pulmonary infiltrates without hilar lymphadenopathy
Stage 4 disease	Pulmonary fibrosis	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][5]. 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).

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][17]. 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


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][22].

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][7,23].

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][24]. 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][1].

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][25].

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 ^[

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][5,9,25].

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][25]. 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][26].

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][26].

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][9,26].