**Clinical Manifestations of Sarcoidosis**

Luis Jara-Palomares, Candela Caballero-Eraso, Cesar Gutiérrez, Alvaro Donate and Jose Antonio Rodríguez-Portal

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55556

### **1. Introduction**

Sarcoidosis is a systemic granulomatous disease of unknown etiology that is characterized from the point of view of pathology of the presence of noncaseating granulomas in affected organs. Typically affects young adults and is often present initially with one or more of the following conditions: 1) bilateral hilar lymphadenopathy, 2) pulmonary reticular pattern, 3) Involvement of the skin, joints and / or eyes.

In this chapter we are going to review and update the clinical features and sign of sarcoidosis.

### **2. Airway involvement**

Patients with pulmonary sarcoidosis may have impaired upper and/or lower airway, and could be impossible or difficult to detect with routine imaging, but are recognized by alterna‐ tive diagnostic tests (eg, bronchoscopy) [1]. Endobronchial disease exists in approximately 40% of patients with stage I disease, and approximately 70% of patients with stage II or III. Airway stenosis clinically significant is rare but can be unwieldy when severe [2, 3]. Table 1 summarize the airway involvement in sarcoidosis.

In the fibrotic stage of the disease can be observed thinning of the mucosa, pallor, and scarring can lead to a decrease in the light of the airways and the stenosis [4-6].

© 2013 Jara-Palomares et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Obstructive sleep apnea, which occurs in about 5% of the general population, seems to occur with increased frequency in patients with sarcoidosis, especially in patients with lupus pernio [18]. Sarcoidosis of the upper airways has been suggested as one of the possible mechanisms for sleep apnea in patients with sarcoidosis and lupus pernio, although the overwhelming majority of obstructive sleep apnea in sarcoidosis is most probably related to obesity from

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 111

Laryngeal sarcoidosis often occurs as an isolated phenomenon and is usually attributed to asthma [20]. Occasionally, laryngeal sarcoid can lead to progressive life-threatening airway obstruction [15]. Laryngeal sarcoidosis is uncommon [21]. The incidence of laryngeal sarcoi‐ dosis is estimated to be about 1.2%. Laryngeal sarcoidosis could be treated with systemic and intralesional injections of a corticosteroid, surgical intervention, carbon dioxide laser ablation,

Paralysis of the left vocal cord and hoarseness can occur from compression of the left recurrent laryngeal nerve by enlarged lymph nodes [24, 25]. Systemic corticosteroid therapy has resulted

The trachea and main bronchi are less frequently affected than the lobar, segmental, subseg‐ mental, and distal airways. Sarcoid granulomas of trachea, main carina, and major bronchi by themselves seldom produce significant obstructive symptoms or airway dysfunction [26, 27]. Cough is the main symptom. Symptoms, clinical examination, flow-volume curves, and

Mainstem bronchial stenoses as well as segmental stenosis have been described in patients with sarcoidosis [29]. Disabling inspiratory and expiratory airflow limitation mimicking fixed upper airway obstruction has been reported [27]. Bronchoscopy may demonstrate other changes as: mucosal erythema, edema, friability, granularity, fine cobblestoning, and sarcoid nodules. The characteristic yellow waxy nodules typical of sarcoidosis are less likely to occur in the trachea and main bronchi, but when seen in these areas, they tend to be sparsely

Extrinsic compression of the central airways by the enlarged mediastinal and hilar lymph nodes is uncommon. Right middle lobe syndrome caused by extrinsic compression and

Sarcoidosis could affect lobar, segmental, subsegmental, and more distal bronchi as well as bronchioles, which is manifested as mucosal inflammation, endobronchial granulomas, stenosis, extrinsic compression, distortion, bronchiectasis, bronchiolitis, airway hyperreactiv‐

bronchoscopy help in assessing the severity of the central airway stenosis [28].

corticosteroids. Sarcoidosis of the supraglottic airways in children is rare [19].

**2.2. Larynx**

and external beam radiation [22, 23].

in resolution of the hoarseness [24].

intraluminal sarcoidosis has been described [30].

**2.3. Central airways**

distributed.

**2.4. Distal airways**

ity, and streaky hemoptysis.

\*A biopsy required to document the presence of a noncaseous granuloma; in other types of involvement, a biopsy specimen may or may not demonstrate noncaseous granulomas.

Modified from Ref. 1

**Table 1.** Airway involvement in sarcoidosis

#### **2.1. Supraglottic airways**

Nasal passages, oropharynx, supraglottic structures, and the larynx develop sarcoid granulo‐ mas in approximately 6% of patients with sarcoidosis [7-10]. Debería sospecharse en todos los pacientes con sarcoidosis sistémica y síntomas de vía aérea superior [4, 5, 8, 11-12]. Sarcoid lesions can occur in nasal and oral mucosa, occasionally with ulceration; anosmia improves after steroid therapy [13]. A nasal examination may reveal granulomatous mass, yellow-white mucosal papules, and adhesions and crusting of septal and turbinate mucosa. Nodular sarcoidosis of supraglottic and glottic structures can lead to dyspnea, stridor, dysphonia, irritating cough with pharyngolaryngeal discomfort, dysphagia, retronasal obstruction, and/or hyponasal speech. Rhinopharyngolaryngeal endoscopy may reveal reddish or yellow granulomatous lesions (2-4 mm in diameter) [14]. Laryngoscopy may show epiglottic thick‐ ening and granularity, granulomatous mass and infiltrative sarcoid nodules of epiglottis, aryepiglottic folds, and false cords. These may cause respiratory distress, requiring tracheos‐ tomy [15]. Flow-volume curves and laryngeal examination are helpful in the diagnosis and management [16]. Obstructing polypoid sarcoid lesions have been managed with laryngo‐ scopic resection, tracheostomy, or local injection of a corticosteroid [17].

Obstructive sleep apnea, which occurs in about 5% of the general population, seems to occur with increased frequency in patients with sarcoidosis, especially in patients with lupus pernio [18]. Sarcoidosis of the upper airways has been suggested as one of the possible mechanisms for sleep apnea in patients with sarcoidosis and lupus pernio, although the overwhelming majority of obstructive sleep apnea in sarcoidosis is most probably related to obesity from corticosteroids. Sarcoidosis of the supraglottic airways in children is rare [19].

### **2.2. Larynx**

**Type of involvement Comments** Mucosal erythema and edema Nonspecific finding\* Granular mucosa Nonspecific\*

Mucosal nodules (waxy

Airflow limitation (FEV1/FVC ratio < 80)

Modified from Ref. 1

**Table 1.** Airway involvement in sarcoidosis

**2.1. Supraglottic airways**

yellow)

110 Sarcoidosis

Cobblestone mucosa More common in lobar and segmental bronchi\*

Airway distortion More likely in advanced parenchymal disease

asymptomatic Bronchiolitis Uncommon; CT scan may suggest diagnosis\*

risk

Hemoptysis Uncommon from airway involvement

specimen may or may not demonstrate noncaseous granulomas.

Characteristic feature\*; may occlude bronchi

Bronchial stenosis Lobar and segmental bronchi affected more frequently than central airways; mucosal biopsy may or may not show granulomas

Bronchiectasis Traction bronchiectasis associated with advanced parenchymal disease; usually

Airway hyperreactivity Occurs in up to 20% of sarcoid patients; endobronchial involvement increases the

Obstructive sleep apnea Due to laryngeal involvement; more common in patients with lupus pernio Supraglottic structures Oral, nasal, and pharyngeal mucosal changes as noted above, hoarseness,

Occurs in 60% of sarcoid patients; seen in any stage

dysphagia, laryngeal paralysis, and airway obstruction

\*A biopsy required to document the presence of a noncaseous granuloma; in other types of involvement, a biopsy

Nasal passages, oropharynx, supraglottic structures, and the larynx develop sarcoid granulo‐ mas in approximately 6% of patients with sarcoidosis [7-10]. Debería sospecharse en todos los pacientes con sarcoidosis sistémica y síntomas de vía aérea superior [4, 5, 8, 11-12]. Sarcoid lesions can occur in nasal and oral mucosa, occasionally with ulceration; anosmia improves after steroid therapy [13]. A nasal examination may reveal granulomatous mass, yellow-white mucosal papules, and adhesions and crusting of septal and turbinate mucosa. Nodular sarcoidosis of supraglottic and glottic structures can lead to dyspnea, stridor, dysphonia, irritating cough with pharyngolaryngeal discomfort, dysphagia, retronasal obstruction, and/or hyponasal speech. Rhinopharyngolaryngeal endoscopy may reveal reddish or yellow granulomatous lesions (2-4 mm in diameter) [14]. Laryngoscopy may show epiglottic thick‐ ening and granularity, granulomatous mass and infiltrative sarcoid nodules of epiglottis, aryepiglottic folds, and false cords. These may cause respiratory distress, requiring tracheos‐ tomy [15]. Flow-volume curves and laryngeal examination are helpful in the diagnosis and management [16]. Obstructing polypoid sarcoid lesions have been managed with laryngo‐

scopic resection, tracheostomy, or local injection of a corticosteroid [17].

Extrinsic compression Uncommon; may occur with significant thoracic lymphadenopathy

Mucosal plaques (yellowish) Also occurs in other disorders\*

Laryngeal sarcoidosis often occurs as an isolated phenomenon and is usually attributed to asthma [20]. Occasionally, laryngeal sarcoid can lead to progressive life-threatening airway obstruction [15]. Laryngeal sarcoidosis is uncommon [21]. The incidence of laryngeal sarcoi‐ dosis is estimated to be about 1.2%. Laryngeal sarcoidosis could be treated with systemic and intralesional injections of a corticosteroid, surgical intervention, carbon dioxide laser ablation, and external beam radiation [22, 23].

Paralysis of the left vocal cord and hoarseness can occur from compression of the left recurrent laryngeal nerve by enlarged lymph nodes [24, 25]. Systemic corticosteroid therapy has resulted in resolution of the hoarseness [24].

#### **2.3. Central airways**

The trachea and main bronchi are less frequently affected than the lobar, segmental, subseg‐ mental, and distal airways. Sarcoid granulomas of trachea, main carina, and major bronchi by themselves seldom produce significant obstructive symptoms or airway dysfunction [26, 27]. Cough is the main symptom. Symptoms, clinical examination, flow-volume curves, and bronchoscopy help in assessing the severity of the central airway stenosis [28].

Mainstem bronchial stenoses as well as segmental stenosis have been described in patients with sarcoidosis [29]. Disabling inspiratory and expiratory airflow limitation mimicking fixed upper airway obstruction has been reported [27]. Bronchoscopy may demonstrate other changes as: mucosal erythema, edema, friability, granularity, fine cobblestoning, and sarcoid nodules. The characteristic yellow waxy nodules typical of sarcoidosis are less likely to occur in the trachea and main bronchi, but when seen in these areas, they tend to be sparsely distributed.

Extrinsic compression of the central airways by the enlarged mediastinal and hilar lymph nodes is uncommon. Right middle lobe syndrome caused by extrinsic compression and intraluminal sarcoidosis has been described [30].

#### **2.4. Distal airways**

Sarcoidosis could affect lobar, segmental, subsegmental, and more distal bronchi as well as bronchioles, which is manifested as mucosal inflammation, endobronchial granulomas, stenosis, extrinsic compression, distortion, bronchiectasis, bronchiolitis, airway hyperreactiv‐ ity, and streaky hemoptysis.

These can lead to airway dysfunction and respiratory symptoms. Sarcoid granulomas tend to develop along the bronchovascular bundle or in the vicinity of the airways. All of these changes are more likely to affect the airways in upper and mid-lung regions.

been described [42]. Traction bronchiectasis and bronchial distortion, as described earlier,

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 113

Hemoptysis in patients with sarcoidosis is usually the result of a complication such as the development of an aspergilloma in advanced fibrotic and cavitary sarcoid [44-46]. Large pulmonary cystic lesions occur in advanced stages of sarcoidosis, and these could potentially become infected with *Aspergillus* and aspergilloma could develop. Fatal massive hemoptysis has been described in such patients [46]. Traction bronchiectasis is observed in patients with

Airway hyperreactivity has been reported in up to 20% of patients with sarcoidosis, and, as a result, cough and wheezing may prompt patients to seek medical help [47, 48]. The airway hyperreactivity is also responsible for the cough, wheezing, and dyspnea and is independent of the airway involvement. Airway hyperreactivity in patients with sarcoidosis remains a difficult entity to define because of the airway involvement by sarcoidosis. The smaller baseline diameter of the diseased airway can potentially increase airway resistance and lead to a false-

Bronchoscopy plays a significant role in the diagnosis and management of airway sarcoidosis. The role of the technique in the retrieval of immune effector cells and infectious organisms by analyzing bronchoalveolar lavage (BAL) fluid, biopsy specimens of pulmonary parenchymal sarcoid, and needle aspiration/biopsy samples of enlarged lymph nodes in the mediastinum and hilar regions is well known [49]. These bronchoscopic techniques have an important role in the diagnosis of infectious diseases in sarcoid patients in whom complications such as aspergilloma and other infections develop. Bronchoscopy also helps in excluding disorders

Bronchoscopic abnormalities have been observed in up to 60% of patients with sarcoidosis [48]. These include "retinalization" of mucosa from increased mucosal vascularity, mucosal coarseness, pallor, flat yellow mucosal plaques, wartlike excrescences, "bleb-like" formations, irregular mucosal thickening, ulceration, and atrophic mucosa. The three common findings were bronchial mucosal hyperemia or edema, distortion of the bronchial anatomy, and bronchial narrowing. The classic endobronchial sarcoidosis is mucosal islands of waxy yellow mucosal nodules, 2 to 4 mm in diameter. Bronchoscopy may reveal endobronchial occlusion by sarcoid granulomas in the submucosa or an endobronchial polyp caused by sarcoid

Bronchoscopic biopsy of endobronchial lesions confirms the diagnosis of endobronchial sarcoidosis in up to 70% patients with the disease [48, 50, 51]. Patients with abnormalappearing airways are much more likely to have positive results, with a diagnostic yield of 75% [48]. Even when the airway mucosa appears normal, mucosal biopsy specimens may

advanced sarcoidosis and endobronchial sarcoidosis rarely causes hemoptysis.

seldom cause bronchiectatic symptoms [43].

**f.** Hemoptysis

**g.** Airway Hyperreactivity

**2.5. Bronchoscopy**

granulomas [35].

positive bronchoprovocation test result.

that may resemble sarcoidosis.

The various types of airway abnormalities encountered in patients with sarcoidosis are described in the following paragraphs.

#### **a.** Endobronchial Granulomas

The definitive diagnosis of endobronchial granulomata requires a biopsy of the airway mucosa because a normal-appearing airway mucosa does not exclude the presence of granulomas [31]. The mucosal abnormalities can be diffuse or patchy. These findings are nonspecific and may be seen in other disorders. Therefore, biopsies of the mucosa and submucosa are essential for making a histologic diagnosis. Segmental and lobar bronchial lumen can be compromised by extrinsic compression by an enlarged adjacent lymph node. Endobronchial characteristics of sarcoid granulomas are well documented [32]. The classic endobronchial sarcoidosis is characterized by mucosal islands of waxy yellow mucosal nodules, measuring 2 to 4 mm in diameter. These nodules appear dull gray or waxy yellow. The mucosal lesions tend to be diffuse but more profuse in the lobar and segmental bronchi. Bronchial luminal occlusion by sarcoid granulomas can mimic an obstructing malignant mass. Endobronchial granulomas produce cough, wheezing, and dyspnea. The mucosal nodules seldom ulcerate or bleed.

#### **b.** Bronchial Stenosis

Bronchial stenosis is reported to occur in up to 14% of patients with sarcoidosis [33]. Bron‐ choscopy is helpful in evaluating the location, types, and severity of bronchial stenosis. The stenoses can be solitary or multiple, lobar or segmental bronchial stenoses, with or without atelectasis, and they may occur at any stage of respiratory sarcoidosis [33-35]. Extensive and multiple stenotic lesions of larger bronchi may cause or contribute to pulmonary symptoms.

#### **c.** Bronchiolitis

Bronchiolar involvement from sarcoidosis can also occur in early sarcoidosis without pulmo‐ nary parenchymal involvement [36, 37]. Bronchiolitis obliterans organizing pneumonia, bronchiolar narrowing and occlusion, and sarcoidosis coexisting with asthma have been described [38, 39]. Airtrapping is a common feature in sarcoidosis and correlates with evidence of small airways disease on pulmonary function testing.

#### **d.** Airway Distortion

Airway distortion is common in later stages of sarcoidosis and is caused by granulomatous changes in and around the airways and the secondary traction bronchiectasis associated with pulmonary parenchymal fibrosis [40, 41].

#### **e.** Bronchiectasis

Traction bronchiectasis becomes evident as the parenchymal disease progresses [40]. Traction bronchiectasis has been reported in up to 40% of patients with fibrotic stages of sarcoid [41]. Localized bronchiectasis of the right middle lobe caused by obstructing sarcoid granuloma has been described [42]. Traction bronchiectasis and bronchial distortion, as described earlier, seldom cause bronchiectatic symptoms [43].

#### **f.** Hemoptysis

These can lead to airway dysfunction and respiratory symptoms. Sarcoid granulomas tend to develop along the bronchovascular bundle or in the vicinity of the airways. All of these changes

The various types of airway abnormalities encountered in patients with sarcoidosis are

The definitive diagnosis of endobronchial granulomata requires a biopsy of the airway mucosa because a normal-appearing airway mucosa does not exclude the presence of granulomas [31]. The mucosal abnormalities can be diffuse or patchy. These findings are nonspecific and may be seen in other disorders. Therefore, biopsies of the mucosa and submucosa are essential for making a histologic diagnosis. Segmental and lobar bronchial lumen can be compromised by extrinsic compression by an enlarged adjacent lymph node. Endobronchial characteristics of sarcoid granulomas are well documented [32]. The classic endobronchial sarcoidosis is characterized by mucosal islands of waxy yellow mucosal nodules, measuring 2 to 4 mm in diameter. These nodules appear dull gray or waxy yellow. The mucosal lesions tend to be diffuse but more profuse in the lobar and segmental bronchi. Bronchial luminal occlusion by sarcoid granulomas can mimic an obstructing malignant mass. Endobronchial granulomas produce cough, wheezing, and dyspnea. The mucosal nodules seldom ulcerate or bleed.

Bronchial stenosis is reported to occur in up to 14% of patients with sarcoidosis [33]. Bron‐ choscopy is helpful in evaluating the location, types, and severity of bronchial stenosis. The stenoses can be solitary or multiple, lobar or segmental bronchial stenoses, with or without atelectasis, and they may occur at any stage of respiratory sarcoidosis [33-35]. Extensive and multiple stenotic lesions of larger bronchi may cause or contribute to pulmonary symptoms.

Bronchiolar involvement from sarcoidosis can also occur in early sarcoidosis without pulmo‐ nary parenchymal involvement [36, 37]. Bronchiolitis obliterans organizing pneumonia, bronchiolar narrowing and occlusion, and sarcoidosis coexisting with asthma have been described [38, 39]. Airtrapping is a common feature in sarcoidosis and correlates with evidence

Airway distortion is common in later stages of sarcoidosis and is caused by granulomatous changes in and around the airways and the secondary traction bronchiectasis associated with

Traction bronchiectasis becomes evident as the parenchymal disease progresses [40]. Traction bronchiectasis has been reported in up to 40% of patients with fibrotic stages of sarcoid [41]. Localized bronchiectasis of the right middle lobe caused by obstructing sarcoid granuloma has

of small airways disease on pulmonary function testing.

pulmonary parenchymal fibrosis [40, 41].

are more likely to affect the airways in upper and mid-lung regions.

described in the following paragraphs.

**a.** Endobronchial Granulomas

112 Sarcoidosis

**b.** Bronchial Stenosis

**c.** Bronchiolitis

**d.** Airway Distortion

**e.** Bronchiectasis

Hemoptysis in patients with sarcoidosis is usually the result of a complication such as the development of an aspergilloma in advanced fibrotic and cavitary sarcoid [44-46]. Large pulmonary cystic lesions occur in advanced stages of sarcoidosis, and these could potentially become infected with *Aspergillus* and aspergilloma could develop. Fatal massive hemoptysis has been described in such patients [46]. Traction bronchiectasis is observed in patients with advanced sarcoidosis and endobronchial sarcoidosis rarely causes hemoptysis.

#### **g.** Airway Hyperreactivity

Airway hyperreactivity has been reported in up to 20% of patients with sarcoidosis, and, as a result, cough and wheezing may prompt patients to seek medical help [47, 48]. The airway hyperreactivity is also responsible for the cough, wheezing, and dyspnea and is independent of the airway involvement. Airway hyperreactivity in patients with sarcoidosis remains a difficult entity to define because of the airway involvement by sarcoidosis. The smaller baseline diameter of the diseased airway can potentially increase airway resistance and lead to a falsepositive bronchoprovocation test result.

#### **2.5. Bronchoscopy**

Bronchoscopy plays a significant role in the diagnosis and management of airway sarcoidosis. The role of the technique in the retrieval of immune effector cells and infectious organisms by analyzing bronchoalveolar lavage (BAL) fluid, biopsy specimens of pulmonary parenchymal sarcoid, and needle aspiration/biopsy samples of enlarged lymph nodes in the mediastinum and hilar regions is well known [49]. These bronchoscopic techniques have an important role in the diagnosis of infectious diseases in sarcoid patients in whom complications such as aspergilloma and other infections develop. Bronchoscopy also helps in excluding disorders that may resemble sarcoidosis.

Bronchoscopic abnormalities have been observed in up to 60% of patients with sarcoidosis [48]. These include "retinalization" of mucosa from increased mucosal vascularity, mucosal coarseness, pallor, flat yellow mucosal plaques, wartlike excrescences, "bleb-like" formations, irregular mucosal thickening, ulceration, and atrophic mucosa. The three common findings were bronchial mucosal hyperemia or edema, distortion of the bronchial anatomy, and bronchial narrowing. The classic endobronchial sarcoidosis is mucosal islands of waxy yellow mucosal nodules, 2 to 4 mm in diameter. Bronchoscopy may reveal endobronchial occlusion by sarcoid granulomas in the submucosa or an endobronchial polyp caused by sarcoid granulomas [35].

Bronchoscopic biopsy of endobronchial lesions confirms the diagnosis of endobronchial sarcoidosis in up to 70% patients with the disease [48, 50, 51]. Patients with abnormalappearing airways are much more likely to have positive results, with a diagnostic yield of 75% [48]. Even when the airway mucosa appears normal, mucosal biopsy specimens may demonstrate mucosal or submucosal noncaseous granulomas in up to 50% of patients with sarcoidosis [48]. In typical cases, the identification of noncaseous granulomas on frozen section analysis may render lung biopsy unnecessary.

**•** Stage IV: Is characterized by reticular opacities with evidence of volume loss, chiefly distributed in the upper lobes. Can also be observed: adenopathic clusters with marked

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 115

Sarcoidosis patient can show a variety of abnormalities [58, 59]: Hilar and mediastinal lymphadenopathy, beaded or irregular thickening of the bronchovascular bundles, nodules along bronchi, vessels, and subpleural regions, bronchial wall thickening, ground glass opacification, parenchymal masses or consolidation, parenchymal bands, cysts, traction

High-resolution CT has proved superior to conventional CT for assessing subtle parenchymal details and discriminating between inflammation and fibrosis in patients with pulmonary

traction bronchiectasis, or extensive calcification, cavitation or cyst formation [57].

**Figure 1.** Staging of sarcoidosis on basis of chest radiographs

**b.** Computerized Axial Tomography (CT) scan:

bronchiectasis, fibrosis with distortion of the lung architecture.

### **3. Lung disease**

Sarcoidosis occurs in patients aged between 10-40 years in 70-90% of cases. In about half the cases the disease is detected incidentally by alterations in the chest radiograph. The organ most frequently affected is the lung. The most common symptoms are cough, dyspnea and chest pain. In patients in the eighth decade of life is more common than systemic symptoms such as fatigue and anorexia, although dyspnea is often present at the same time [52].

A pulmonary auscultation crackles or roncus uncommon to hear, but wheezing may be present.

#### **3.1. Pulmonary imaging**

Pulmonary involvement occurs in 90% of patients with sarcoidosis [10]. The typical chest radiograph shows bilateral hilar lymphadenopathy. This finding, however, may be absent, or if present may occur in combination with opacities in the parenchyma. Parenchymal opacities may be interstitial, alveolar or both. Pleural involvement is uncommon (<5%), but may occur as lymphocytic exudate in the pleural effusion, chylothorax, hemothorax, or pneumothorax [54-56].

#### **a.** Chest x-ray:

Stage of lung involvement is established based on chest radiography. Although the chest radiograph provides an anatomical guide of lung disease can not measure disease activity or functional damage assessment. The sarcoid nodule is defined as pulmonary nodules, bilateral and multiple in the chest radiograph, which may mimic metastatic disease. When viewed through the computerized tomography (CT) revealed a nodular consolidation with well defined borders [56]. Radiological stages are (Figure 1):


**•** Stage IV: Is characterized by reticular opacities with evidence of volume loss, chiefly distributed in the upper lobes. Can also be observed: adenopathic clusters with marked traction bronchiectasis, or extensive calcification, cavitation or cyst formation [57].

**Figure 1.** Staging of sarcoidosis on basis of chest radiographs

demonstrate mucosal or submucosal noncaseous granulomas in up to 50% of patients with sarcoidosis [48]. In typical cases, the identification of noncaseous granulomas on frozen section

Sarcoidosis occurs in patients aged between 10-40 years in 70-90% of cases. In about half the cases the disease is detected incidentally by alterations in the chest radiograph. The organ most frequently affected is the lung. The most common symptoms are cough, dyspnea and chest pain. In patients in the eighth decade of life is more common than systemic symptoms such as

A pulmonary auscultation crackles or roncus uncommon to hear, but wheezing may be

Pulmonary involvement occurs in 90% of patients with sarcoidosis [10]. The typical chest radiograph shows bilateral hilar lymphadenopathy. This finding, however, may be absent, or if present may occur in combination with opacities in the parenchyma. Parenchymal opacities may be interstitial, alveolar or both. Pleural involvement is uncommon (<5%), but may occur as lymphocytic exudate in the pleural effusion, chylothorax, hemothorax, or pneumothorax

Stage of lung involvement is established based on chest radiography. Although the chest radiograph provides an anatomical guide of lung disease can not measure disease activity or functional damage assessment. The sarcoid nodule is defined as pulmonary nodules, bilateral and multiple in the chest radiograph, which may mimic metastatic disease. When viewed through the computerized tomography (CT) revealed a nodular consolidation with well

**•** Stage I: is defined as the presence of bilateral hilar lymphadenopathy, which are often accompanied with an increase in right paratracheal adenopathy. 50% of patients initially present as bilateral hilar lymphadenopathy. In 75% of cases, hilar lymphadenopathy return

**•** Stage II: Defined as bilateral hilar lymphadenopathy and reticular opacities (the latter occurs more often in the upper lobes). These findings are initially in 25% of patients. In two thirds of these cases the lesions regress spontaneously, while the rest can be progression of the disease or remain unchanged over time. Normally the stage II patients have mild or moderate. The most common symptoms are usually: cough, dyspnea, fever, and/or fatigue. **•** Stage III: This is defined as reticular opacities without hilar lymphadenopathy. Reticular

within the first through third year, while 10% will persist for 10 years or more.

defined borders [56]. Radiological stages are (Figure 1):

opacities are distributed predominantly in the upper lobes.

fatigue and anorexia, although dyspnea is often present at the same time [52].

analysis may render lung biopsy unnecessary.

**3. Lung disease**

**3.1. Pulmonary imaging**

present.

114 Sarcoidosis

[54-56].

**a.** Chest x-ray:

**b.** Computerized Axial Tomography (CT) scan:

Sarcoidosis patient can show a variety of abnormalities [58, 59]: Hilar and mediastinal lymphadenopathy, beaded or irregular thickening of the bronchovascular bundles, nodules along bronchi, vessels, and subpleural regions, bronchial wall thickening, ground glass opacification, parenchymal masses or consolidation, parenchymal bands, cysts, traction bronchiectasis, fibrosis with distortion of the lung architecture.

High-resolution CT has proved superior to conventional CT for assessing subtle parenchymal details and discriminating between inflammation and fibrosis in patients with pulmonary sarcoidosis [58, 60]. The thin-section collimation (1- to 1.5- mm section thickness) and highspatial-frequency reconstruction algorithms that are used to generate high-resolution CT images allow improved detection of nodular and reticular opacities, thickened interlobular septa, and faint ground-glass opacities, making the technique especially useful for identifying and managing sarcoidosis.

**•** Typical Patterns of Lymphadenopathy

approximately 50% of patients [60].

signs and symptoms develop [67].

patients with sarcoidosis.

middle zones, in a patchy distribution [41].

ment, and attenuation of peripheral vessels.

**3.** Bilateral Perihilar Opacities

**2.** Fibrotic Changes

**•** Typical Parenchymal Manifestations

**1.** Micronodules with a Perilymphatic Distribution

The most common pattern is well-defined, bilateral, symmetric hilar and right paratracheal lymph node enlargement. Bilateral hilar lymph node enlargement, alone or in combination with mediastinal lymph node enlargement, occurs in an estimated 95% of patients affected with sarcoidosis [65, 66]. Middle mediastinal nodes (at the left paratracheal level, subcarinal level, and level of the aortopulmonary window), prevascular nodes, or both are involved in

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 117

Bilateral hilar lymph node enlargement may be a feature of infection (particularly fungal or mycobacterial infection) or malignancy (eg, lymphoma). However, in the absence of specific symptoms or signs, sarcoidosis is the most common cause of bilateral lymph node enlarge‐ ment. Histologic confirmation is not required for a diagnosis of sarcoidosis in these patients. However, a biopsy should be performed if the chest radiographic findings worsen or specific

A perilymphatic distribution of micronodular lesions is the most common parenchymal disease pattern seen in patients with pulmonary sarcoidosis (75%–90% of cases). High-resolution CT shows sharply defined, small (2–4 mm in diameter), rounded nodules, usually with a bilateral and symmetric distribution, predominantly but not invariably in the upper and middle zones. The nodules are found most often in the subpleural peribronchovascular interstitium and less often in the interlobular septa. Although sarcoid granulomas arise as micronodular lesions, they

Sarcoid granulomas frequently cause nodular or irregular thickening of the peribronchovas‐ cular interstitium. Extensive peribronchovascular nodularity on high-resolution CT images is strongly suggestive of sarcoidosis. However, interstitial thickening is not extensive in most

In most patients, sarcoid granulomas resolve with time. However, in an estimated 20% of patients, fibrosis becomes more prominent over time, producing CT and radiographic findings of linear opacities, traction bronchiectasis, and architectural distortion (displacement of fissures and bronchovascular bundles). Fibrosis is seen predominantly in the upper and

Extensive interstitial fibrosis can cause pulmonary arterial hypertension and resultant right heart failure. Imaging findings that may be predictive of such an event include a prominent main pulmonary artery, enlarged right and left pulmonary arteries, right ventricular enlarge‐

Confluent nodular opacities that appear on high-resolution CT images as bilateral areas of lung consolidation with irregular edges and blurred margins, radiating from the hilum toward

may coalesce over time, forming larger lesions (macronodules) [56, 58, 63].

High-resolution CT may be particularly helpful for distinguishing active inflammation from irreversible fibrosis in selected patients with stage 2 or 3 sarcoidosis. Nodules, ground-glass opacities, and alveolar opacities are suggestive of granulomatous inflammation that may be reversed with therapy [61]. By contrast, honeycomb-like cysts, bullae, broad and coarse septal bands, architectural distortion, volume loss, and traction bronchiectasis are indicative of irreversible fibrosis [62]. High-resolution CT may be useful also for verifying specific diagnoses in patients with atypical clinical manifestations or unusual radiographic features [63].

In the appropriate clinical context, the observation of typical imaging features of sarcoidosis (eg, bilateral hilar lymph node enlargement with a perilymphatic micronodular pattern) and the anatomic distribution of those abnormalities (eg, upper lobe predominance) may point to a highly specific diagnosis. However, atypical manifestations may necessitate a broader differential diagnosis that includes tuberculosis and other granulomatous infections, silicosis, malignancies, and pneumoconiosis.

We are going to explain some typical patterns of sarcoidosis. Criado et al. [64] published and extensive review about typical and typical patterns of sarcoidosis. Table 2 shows typical and atypical features of pulmonary sarcoidosis at high-resolution CT.


**Table 2.** Typical and Atypical Features of Pulmonary Sarcoidosis at High-Resolution CT. Modified from ref. 64.

**•** Typical Patterns of Lymphadenopathy

sarcoidosis [58, 60]. The thin-section collimation (1- to 1.5- mm section thickness) and highspatial-frequency reconstruction algorithms that are used to generate high-resolution CT images allow improved detection of nodular and reticular opacities, thickened interlobular septa, and faint ground-glass opacities, making the technique especially useful for identifying

High-resolution CT may be particularly helpful for distinguishing active inflammation from irreversible fibrosis in selected patients with stage 2 or 3 sarcoidosis. Nodules, ground-glass opacities, and alveolar opacities are suggestive of granulomatous inflammation that may be reversed with therapy [61]. By contrast, honeycomb-like cysts, bullae, broad and coarse septal bands, architectural distortion, volume loss, and traction bronchiectasis are indicative of irreversible fibrosis [62]. High-resolution CT may be useful also for verifying specific diagnoses in patients with atypical clinical manifestations or unusual radiographic features [63].

In the appropriate clinical context, the observation of typical imaging features of sarcoidosis (eg, bilateral hilar lymph node enlargement with a perilymphatic micronodular pattern) and the anatomic distribution of those abnormalities (eg, upper lobe predominance) may point to a highly specific diagnosis. However, atypical manifestations may necessitate a broader differential diagnosis that includes tuberculosis and other granulomatous infections, silicosis,

We are going to explain some typical patterns of sarcoidosis. Criado et al. [64] published and extensive review about typical and typical patterns of sarcoidosis. Table 2 shows typical and

Lymphadenopathy: unilateral, isolated, anterior and

Airspace consolidation: masslike opacities, conglomerate masses, solitary pulmonary nodules, confluent alveolar opacities (alveolar sarcoid pattern)

Linear opacities: interlobular septal thickening,

Fibrocystic changes: cysts, bullae, blebs, emphysema, honeycomb-like opacities with upper- and middle-zone

Airway involvement: mosaic attenuation pattern, tracheobronchial abnormalities, atelectasis Pleural disease: effusion, chylothorax, hemothorax, pneumothorax, pleural thickening, calcification

posterior mediastinal

intralobular linear opacities

predominance

Miliary opacities

Mycetoma, aspergilloma

atypical features of pulmonary sarcoidosis at high-resolution CT.

**Typical features Atypical features**

Bilateral perihilar opacities Ground-glass opacities

**Table 2.** Typical and Atypical Features of Pulmonary Sarcoidosis at High-Resolution CT. Modified from ref. 64.

and managing sarcoidosis.

116 Sarcoidosis

malignancies, and pneumoconiosis.

Lymphadenopathy: hilar, mediastinal (right paratracheal), bilateral, symmetric, and well defined

coalescing)

volume loss

interlobular septal

parenchymal abnormalities

Nodules: micronodules (2–4 mm in diameter; well defined, bilateral); macronodules (≥5 mm in diameter,

Fibrotic changes: reticular opacities, architectural distortion, traction bronchiectasis, bronchio-lectasis,

Predominant upper- and middle-zone locations of

Lymphangitic spread: peribronchovascular, subpleural,

The most common pattern is well-defined, bilateral, symmetric hilar and right paratracheal lymph node enlargement. Bilateral hilar lymph node enlargement, alone or in combination with mediastinal lymph node enlargement, occurs in an estimated 95% of patients affected with sarcoidosis [65, 66]. Middle mediastinal nodes (at the left paratracheal level, subcarinal level, and level of the aortopulmonary window), prevascular nodes, or both are involved in approximately 50% of patients [60].

Bilateral hilar lymph node enlargement may be a feature of infection (particularly fungal or mycobacterial infection) or malignancy (eg, lymphoma). However, in the absence of specific symptoms or signs, sarcoidosis is the most common cause of bilateral lymph node enlarge‐ ment. Histologic confirmation is not required for a diagnosis of sarcoidosis in these patients. However, a biopsy should be performed if the chest radiographic findings worsen or specific signs and symptoms develop [67].


A perilymphatic distribution of micronodular lesions is the most common parenchymal disease pattern seen in patients with pulmonary sarcoidosis (75%–90% of cases). High-resolution CT shows sharply defined, small (2–4 mm in diameter), rounded nodules, usually with a bilateral and symmetric distribution, predominantly but not invariably in the upper and middle zones. The nodules are found most often in the subpleural peribronchovascular interstitium and less often in the interlobular septa. Although sarcoid granulomas arise as micronodular lesions, they may coalesce over time, forming larger lesions (macronodules) [56, 58, 63].

Sarcoid granulomas frequently cause nodular or irregular thickening of the peribronchovas‐ cular interstitium. Extensive peribronchovascular nodularity on high-resolution CT images is strongly suggestive of sarcoidosis. However, interstitial thickening is not extensive in most patients with sarcoidosis.

**2.** Fibrotic Changes

In most patients, sarcoid granulomas resolve with time. However, in an estimated 20% of patients, fibrosis becomes more prominent over time, producing CT and radiographic findings of linear opacities, traction bronchiectasis, and architectural distortion (displacement of fissures and bronchovascular bundles). Fibrosis is seen predominantly in the upper and middle zones, in a patchy distribution [41].

Extensive interstitial fibrosis can cause pulmonary arterial hypertension and resultant right heart failure. Imaging findings that may be predictive of such an event include a prominent main pulmonary artery, enlarged right and left pulmonary arteries, right ventricular enlarge‐ ment, and attenuation of peripheral vessels.

**3.** Bilateral Perihilar Opacities

Confluent nodular opacities that appear on high-resolution CT images as bilateral areas of lung consolidation with irregular edges and blurred margins, radiating from the hilum toward the periphery, are often seen with or without air bronchograms. These areas of consolidation are less homogeneous peripherally and are usually accompanied by micronodules [41, 60].

The greatest value of pulmonary function tests is to verify the course of the disease individually by sequential measurements. Mean it will not detect pulmonary sarcoidosis or provide a reliable estimate of the extent of parenchymal disease. In addition, the clinician can not predict the natural course of lung disease or response to treatment based solely on these tests.

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 119

BAL can be used as an adjuvant as to support the diagnosis of sarcoidosis, showing a reduced number of CD8 cells, an elevated CD4/CD8 ratio and an increase in activated T cells, CD4, immunoglobulins, and IgG-secreting cells [80-83]. BAL may also be useful to exclude infections

Lymphocytosis in BAL is neither sensitive nor specific for the diagnosis of sarcoidosis. In

The D-dimer in BAL also supports the diagnosis of sarcoidosis. An observational study found that 8 of the 10 patients with sarcoidosis had detectable D-dimer in the BAL (defined as Ddimer> 78ng) Compared to none of 18 healthy controls [82]. Among patients with sarcoidosis

The morphological feature of sarcoidosis is the noncaseating granuloma of the lung, which is most often found in the alveolar septa, the walls of the bronchi and pulmonary arteries and veins. Sarcoid granuloma formation probably is preceded by alveolitis which involves more than the interstitium and alveolar spaces is characterized by the accumulation of inflammatory

The sarcoid granuloma is a chronic inflammatory reaction and focal accumulation formed by epithelial cells, monocytes, lymphocytes, macrophages and fibroblasts. Multinucleated giant cells are frequently found between epithelial cells in the follicle of the granuloma and often have cytoplasmic inclusions such as asteroid bodies, Schaumann bodies and birefringent crystalline particles (calcium oxalate and other calcium salts) [86]. Most sarcoid granulomas gradually resolved and leave little or no residual manifestation of prior inflammation.

Health status is a subjective parameter that is being used more frequently to assess health interventions. Questionnaires have been developed, both generic and disease-specific, to assess health status. Differences in patients reported outcomes between sarcoidosis patients with isolated pulmonary involvement and those with extrapulmonary manifestations have not been well described. In this way, Gvozdenovic et al. [68] develop a study to assess the differences of the severity of fatigue and dyspnea symptoms, activities of daily living and health status between the patients with isolated pulmonary and those with pulmonary plus extrapulmonary sarcoidosis. This study concluded that patients with pulmonary and extrap‐ ulmonary sarcoidosis are more fatigued, have more dyspnea, are more limited in their

are more likely to have a higher D-dimer black patients than whites [83].

cells, including monocytes, macrophages and lymphocytes [84, 85].

**3.3. Bronchoalveolar Lavage (BAL)**

addition, this test can be misinterpreted [80].

**3.5. Allocation pulmonary vs. extrapulmonary**

as an alternative diagnosis.

**3.4. Histopathology**

**c.** Positron emission tomography (PET):

A PET fluorine-18-fluorodeoxyglucose (18F-FDG) can help identify occult lesions and poten‐ tially reversible granulomatous disease [69, 70]. This test does not differentiate sarcoidosis from malignant lesions, as 18F-FDG PET can be positive in both processes. However, in a small study of 24 sarcoidosis and 17 lung cancer, the combination of 18F-FDG and 18F-FMT (L- [3-18F]-methyltyrosine) PET scanning was able to differentiate sarcoidosis cancer. Sarcoid lesions were positive in 18 F-FDG PET but negative on 18 F-FMT PET, and both were positive for cancer patients [71]. More studies are needed to confirm these findings. Besides the latter tracer may not be available in all centers.

**d.** Radiotracer scanning - Gallium-67 lung scanning:

Is a noninvasive test for staging the "alveolitis" found in interstitial lung diseases. This compound located the site of inflammation of the lung [72-74]. The role of gallium-67 scanning in the diagnosis and management of sarcoidosis is currently controversial [75]. It has been suggested that there is a direct relationship between a visual index of gallium-67 uptake in the lung and the number of inflammatory cells (particularly macrophages) obtained from bronchoalveolar lavage in patients with sarcoidosis (and idiopathic pulmonary fibrosis). As a result the uptake of gallium-67 may be useful to determine the degree of alveolar inflammation, which will focus more lower alveolar macrophages and neutrophils [72-74].

Unfortunately there has not been adequate study to make any correlation of the gallium-67 level with the stage of swelling or how the level of radionuclide uptake may correspond to the stage of disease. Furthermore, studies in normal subjects demonstrate that there may be a small but significant uptake of gallium-67 in alveolar macrophages obtained by bronchoalveolar lavage despite negative imaging test [76].

As a result, actually is not recommended for routine evaluation with gallium-67 lung scanning in these patients because of the difficulty of interpretation, since it is not specific, and that a negative test does not exclude the disease.

Other types of radiotracer-based scanning may help in future diagnosis and clinical manage‐ ment of patients with sarcoidosis [77, 78]. As an example, one study of 22 patients with sarcoidosis scans performed after administration of technetium-labeled Depreotide, which binds to somatostatin receptors [77]. The scan was positive in 18 patients (81%) and in 4 of whom was negative had a normal chest radiograph. The features of this test are still unknown, and clinical use is experimental.

#### **3.2. Pulmonary function test**

Characteristically, pulmonary function tests show a restrictive pattern with reduced diffusing capacity for carbon monoxide. Yet we must bear in mind that pulmonary function tests may be normal [79]. Endobronchial sarcoidosis may show involvement of airflow obstruction and respiratory pattern.

The greatest value of pulmonary function tests is to verify the course of the disease individually by sequential measurements. Mean it will not detect pulmonary sarcoidosis or provide a reliable estimate of the extent of parenchymal disease. In addition, the clinician can not predict the natural course of lung disease or response to treatment based solely on these tests.

### **3.3. Bronchoalveolar Lavage (BAL)**

the periphery, are often seen with or without air bronchograms. These areas of consolidation are less homogeneous peripherally and are usually accompanied by micronodules [41, 60].

A PET fluorine-18-fluorodeoxyglucose (18F-FDG) can help identify occult lesions and poten‐ tially reversible granulomatous disease [69, 70]. This test does not differentiate sarcoidosis from malignant lesions, as 18F-FDG PET can be positive in both processes. However, in a small study of 24 sarcoidosis and 17 lung cancer, the combination of 18F-FDG and 18F-FMT (L- [3-18F]-methyltyrosine) PET scanning was able to differentiate sarcoidosis cancer. Sarcoid lesions were positive in 18 F-FDG PET but negative on 18 F-FMT PET, and both were positive for cancer patients [71]. More studies are needed to confirm these findings. Besides the latter

Is a noninvasive test for staging the "alveolitis" found in interstitial lung diseases. This compound located the site of inflammation of the lung [72-74]. The role of gallium-67 scanning in the diagnosis and management of sarcoidosis is currently controversial [75]. It has been suggested that there is a direct relationship between a visual index of gallium-67 uptake in the lung and the number of inflammatory cells (particularly macrophages) obtained from bronchoalveolar lavage in patients with sarcoidosis (and idiopathic pulmonary fibrosis). As a result the uptake of gallium-67 may be useful to determine the degree of alveolar inflammation,

Unfortunately there has not been adequate study to make any correlation of the gallium-67 level with the stage of swelling or how the level of radionuclide uptake may correspond to the stage of disease. Furthermore, studies in normal subjects demonstrate that there may be a small but significant uptake of gallium-67 in alveolar macrophages obtained by bronchoalveolar

As a result, actually is not recommended for routine evaluation with gallium-67 lung scanning in these patients because of the difficulty of interpretation, since it is not specific, and that a

Other types of radiotracer-based scanning may help in future diagnosis and clinical manage‐ ment of patients with sarcoidosis [77, 78]. As an example, one study of 22 patients with sarcoidosis scans performed after administration of technetium-labeled Depreotide, which binds to somatostatin receptors [77]. The scan was positive in 18 patients (81%) and in 4 of whom was negative had a normal chest radiograph. The features of this test are still unknown,

Characteristically, pulmonary function tests show a restrictive pattern with reduced diffusing capacity for carbon monoxide. Yet we must bear in mind that pulmonary function tests may be normal [79]. Endobronchial sarcoidosis may show involvement of airflow obstruction and

which will focus more lower alveolar macrophages and neutrophils [72-74].

**c.** Positron emission tomography (PET):

118 Sarcoidosis

tracer may not be available in all centers.

lavage despite negative imaging test [76].

negative test does not exclude the disease.

and clinical use is experimental.

**3.2. Pulmonary function test**

respiratory pattern.

**d.** Radiotracer scanning - Gallium-67 lung scanning:

BAL can be used as an adjuvant as to support the diagnosis of sarcoidosis, showing a reduced number of CD8 cells, an elevated CD4/CD8 ratio and an increase in activated T cells, CD4, immunoglobulins, and IgG-secreting cells [80-83]. BAL may also be useful to exclude infections as an alternative diagnosis.

Lymphocytosis in BAL is neither sensitive nor specific for the diagnosis of sarcoidosis. In addition, this test can be misinterpreted [80].

The D-dimer in BAL also supports the diagnosis of sarcoidosis. An observational study found that 8 of the 10 patients with sarcoidosis had detectable D-dimer in the BAL (defined as Ddimer> 78ng) Compared to none of 18 healthy controls [82]. Among patients with sarcoidosis are more likely to have a higher D-dimer black patients than whites [83].

#### **3.4. Histopathology**

The morphological feature of sarcoidosis is the noncaseating granuloma of the lung, which is most often found in the alveolar septa, the walls of the bronchi and pulmonary arteries and veins. Sarcoid granuloma formation probably is preceded by alveolitis which involves more than the interstitium and alveolar spaces is characterized by the accumulation of inflammatory cells, including monocytes, macrophages and lymphocytes [84, 85].

The sarcoid granuloma is a chronic inflammatory reaction and focal accumulation formed by epithelial cells, monocytes, lymphocytes, macrophages and fibroblasts. Multinucleated giant cells are frequently found between epithelial cells in the follicle of the granuloma and often have cytoplasmic inclusions such as asteroid bodies, Schaumann bodies and birefringent crystalline particles (calcium oxalate and other calcium salts) [86]. Most sarcoid granulomas gradually resolved and leave little or no residual manifestation of prior inflammation.

#### **3.5. Allocation pulmonary vs. extrapulmonary**

Health status is a subjective parameter that is being used more frequently to assess health interventions. Questionnaires have been developed, both generic and disease-specific, to assess health status. Differences in patients reported outcomes between sarcoidosis patients with isolated pulmonary involvement and those with extrapulmonary manifestations have not been well described. In this way, Gvozdenovic et al. [68] develop a study to assess the differences of the severity of fatigue and dyspnea symptoms, activities of daily living and health status between the patients with isolated pulmonary and those with pulmonary plus extrapulmonary sarcoidosis. This study concluded that patients with pulmonary and extrap‐ ulmonary sarcoidosis are more fatigued, have more dyspnea, are more limited in their everyday physical activities, and have lower health status in comparison with those with isolated pulmonary involvement. They proposed several mechanisms to explain these differences, although remained conjectural and are potential fruitful areas for future research.

directly with lung function or PaO2 [92]. When comparing cases of idiopathic pulmonary fibrosis and sarcoidosis there are differences in mPAP of 9 mm Hg for an equivalent functional alteration, so this mechanism does not explain the development of PH in all the patients.

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 121

Few years ago was found that production of endothelin 1 (ET-1) in the lung of patients with sarcoidosis is increased [93]. The ET-1 is a potent vasoconstrictor with mitogenic and inflam‐ matory activity and one of the therapeutic targets for the treatment of PH, using receptor antagonists of ET-1. The synthesis and release of nitric oxide (NO) by endothelial cells causes vasodilatation, the decreased of NO production has been associated with PH. Has been suggested that the decrease of NO, found in some studies of patient with sarcoidosis, may participate in the development of SAPH and that could have therapeutic implications [94].

There is extrinsic compression of major pulmonary arteries by adenopathies up to 21.4% of patients with SAPH and pulmonary fibrosis [95]. This alteration is often seen in cases with mediastinal and bilateral hilIar adenopathies. Compression of the pulmonary vasculature can

Granulomatous involvement of the pulmonary vessel occurs in 69-100% of the cases studied by lung biopsy specimens. Exits occlusive or destructive granulomas or the patient may

We mustn`t forget that myocardial involvement in sarcoidosis occurs in up to 5% of cases and cause ventricular systolic or diastolic failure which contribute to the development of PH [97]. However, the symptomatic myocardial abnormality is lower than that found in necropsy studies. We can conclude that the mechanisms involved in the development of PH in sarcoi‐ dosis are multiple, involving various anatomical structures and with different therapeutic

The diagnosis of PH in sarcoidosis is difficult because the most common symptom is dyspnea, and many times, this symptom is attributed to the presence of parenchymal involvement. The PH should be suspected in patients with sarcoidosis and dyspnea, hypoxemia, or clinical evidence of the presence of right heart failure, particularly, if these symptoms have not a proportional relationship to the degree of parenchymal involvement. Symptoms of right heart failure are independent predictors of increased pressure in the right cavities. However, these symptoms have low sensitivity, and are only manifested in 21% of patients with confirmed PH. The symptoms are: progressive dyspnea, cough, chest pain, palpitations or syncope [98].

develop a perivascular fibrosis. These findings are more frequent in small veins [96].

**b.** Increased vasoreactivity

**c.** Extrinsic compression of pulmonary vessels

also be found in cases of mediastinal fibrosis.

**e.** Post-capillary pulmonary hypertension

Table 4 shows the distribution of the symptoms.

**d.** Vasculopathy

implications.

**4.2. Clinical presentation**

### **4. Pulmonary hypertension complicating sarcoidosis**

Pulmonary hypertension (PH) is defined as the presence of a mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg [87]. Although in most cases sarcoidosis is a disease with good prognosis, the presence of PH is a serious complication that occurs in cases with severe pulmonary involvement, although there have been cases of PH in any stages of the disease. An early diagnosis that may consider different treatment options is critical to improve the prognosis of these patients.

The prevalence of pulmonary hypertension (SAPH) asociated to sarcoidosis is unknown. Prospective and retrospective studies describe prevalence from 5 to 28% [88] (see Table 3). This variability is mainly due to the use of different diagnostic methods, non-homogeneous patient populations and stages of the disease included in those studies. It has been described that in patients with mild lung disease in which PH is defined as that PAP ≥ 40 mm Hg measured by transthoracic echocardiography (TTE), the prevalence is 5.7% [89].


**Table 3.** Ascertained prevalence of Sarcoidosis-associated pulmonary hypertension in several populations

A retrospective study of 53 patients with sarcoidosis and persistent dyspnea showed that in 47% of them had a mPAP ≥ 25 mm Hg. Only 69% of these cases had stage 3-4 of sarcoidosis [90].

#### **4.1. Pathophysiology**

According to Dana Point classification [91] of pulmonary hypertension, the group 3 includes cases of PH due to lung disease or hypoxia (including interstitial lung disease). The group 5 includes the cases where PH has not a clarified mechanism; group 5 also includes sarcoidosis because the pathogenesis of SAPH is associated with complex mechanisms.

**a.** Destruction of the distal capillary bed

Most patients with sarcoidosis and PH are in advanced stages, presenting a significant alteration of lung parenchyma with destruction of the capillary bed and leading of hypoxemia. However, there are cases of SAPH with minimal lung disorder (Stages 0-1) and hemodynamic measurements detected in the right heart catheterization (RHC) are not always correlated directly with lung function or PaO2 [92]. When comparing cases of idiopathic pulmonary fibrosis and sarcoidosis there are differences in mPAP of 9 mm Hg for an equivalent functional alteration, so this mechanism does not explain the development of PH in all the patients.

**b.** Increased vasoreactivity

everyday physical activities, and have lower health status in comparison with those with isolated pulmonary involvement. They proposed several mechanisms to explain these differences, although remained conjectural and are potential fruitful areas for future research.

Pulmonary hypertension (PH) is defined as the presence of a mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg [87]. Although in most cases sarcoidosis is a disease with good prognosis, the presence of PH is a serious complication that occurs in cases with severe pulmonary involvement, although there have been cases of PH in any stages of the disease. An early diagnosis that may consider different treatment options is critical to improve the prognosis of

The prevalence of pulmonary hypertension (SAPH) asociated to sarcoidosis is unknown. Prospective and retrospective studies describe prevalence from 5 to 28% [88] (see Table 3). This variability is mainly due to the use of different diagnostic methods, non-homogeneous patient populations and stages of the disease included in those studies. It has been described that in patients with mild lung disease in which PH is defined as that PAP ≥ 40 mm Hg measured by

**Author/reference Population Number Method Prevalence (%)**

A retrospective study of 53 patients with sarcoidosis and persistent dyspnea showed that in 47% of them had a mPAP ≥ 25 mm Hg. Only 69% of these cases had stage 3-4 of sarcoidosis [90].

According to Dana Point classification [91] of pulmonary hypertension, the group 3 includes cases of PH due to lung disease or hypoxia (including interstitial lung disease). The group 5 includes the cases where PH has not a clarified mechanism; group 5 also includes sarcoidosis

Most patients with sarcoidosis and PH are in advanced stages, presenting a significant alteration of lung parenchyma with destruction of the capillary bed and leading of hypoxemia. However, there are cases of SAPH with minimal lung disorder (Stages 0-1) and hemodynamic measurements detected in the right heart catheterization (RHC) are not always correlated

*Handa (89)* Prospective study of unselected patients 212 TTE 5.7 *Baughmann (88)* Subjects with dyspnea out of proportion 53 RHC 47 *Sulica (98)* Retrospective study of TTE 106 TTE 51

**Table 3.** Ascertained prevalence of Sarcoidosis-associated pulmonary hypertension in several populations

because the pathogenesis of SAPH is associated with complex mechanisms.

**4. Pulmonary hypertension complicating sarcoidosis**

transthoracic echocardiography (TTE), the prevalence is 5.7% [89].

these patients.

120 Sarcoidosis

**4.1. Pathophysiology**

**a.** Destruction of the distal capillary bed

Few years ago was found that production of endothelin 1 (ET-1) in the lung of patients with sarcoidosis is increased [93]. The ET-1 is a potent vasoconstrictor with mitogenic and inflam‐ matory activity and one of the therapeutic targets for the treatment of PH, using receptor antagonists of ET-1. The synthesis and release of nitric oxide (NO) by endothelial cells causes vasodilatation, the decreased of NO production has been associated with PH. Has been suggested that the decrease of NO, found in some studies of patient with sarcoidosis, may participate in the development of SAPH and that could have therapeutic implications [94].

**c.** Extrinsic compression of pulmonary vessels

There is extrinsic compression of major pulmonary arteries by adenopathies up to 21.4% of patients with SAPH and pulmonary fibrosis [95]. This alteration is often seen in cases with mediastinal and bilateral hilIar adenopathies. Compression of the pulmonary vasculature can also be found in cases of mediastinal fibrosis.

**d.** Vasculopathy

Granulomatous involvement of the pulmonary vessel occurs in 69-100% of the cases studied by lung biopsy specimens. Exits occlusive or destructive granulomas or the patient may develop a perivascular fibrosis. These findings are more frequent in small veins [96].

**e.** Post-capillary pulmonary hypertension

We mustn`t forget that myocardial involvement in sarcoidosis occurs in up to 5% of cases and cause ventricular systolic or diastolic failure which contribute to the development of PH [97]. However, the symptomatic myocardial abnormality is lower than that found in necropsy studies. We can conclude that the mechanisms involved in the development of PH in sarcoi‐ dosis are multiple, involving various anatomical structures and with different therapeutic implications.

#### **4.2. Clinical presentation**

The diagnosis of PH in sarcoidosis is difficult because the most common symptom is dyspnea, and many times, this symptom is attributed to the presence of parenchymal involvement. The PH should be suspected in patients with sarcoidosis and dyspnea, hypoxemia, or clinical evidence of the presence of right heart failure, particularly, if these symptoms have not a proportional relationship to the degree of parenchymal involvement. Symptoms of right heart failure are independent predictors of increased pressure in the right cavities. However, these symptoms have low sensitivity, and are only manifested in 21% of patients with confirmed PH. The symptoms are: progressive dyspnea, cough, chest pain, palpitations or syncope [98]. Table 4 shows the distribution of the symptoms.

Sudden death caused by compression of large pulmonary arteries, occlusion of the pulmonary veins by a sarcoid involvement intravascular or combination of SAPH and portal hypertension is infrequent.

**5. Cardiac sarcoidosis**

**5.2. Clinical manifestations**

**5.3. Cardiac arrhythmias**

mias are infrequent.

**5.5. Heart failure**

**5.4. Conduction abnormalities**

conduction disturbances or other cardiac symptoms.

both cases,by the infiltration of the myocardium.

The presence of cardiac sarcoidosis is influenced by race. Over 25% of Japanese sarcoidosis patients present cardiac disease, only 5% of patients in the United States and Europe are affected at this level. Although clinical evidence of myocardial involvement is present in 5% of patients, there are autopsy studies that indicate that sublinical cardiac disease is present in

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 123

Cardiac Sarcoidosis can be an incidental finding, has a benign course or being a life-threatening disorder. Clinicians should suspect this disease in young or middle-aged patients with cardiac symptoms and in any patients with a history of sarcoidosis who develop arrhythmias,

Clinical manifestations depend on the location and extent of granulomatous infiltration, being the most common cause of cardiac involvement secondary to infiltration of the myocardium. Usually, cardiac disease appears with any other organ involvement (lung, skin…). The most frequent manifestations of cardiac sarcoidosis are heart failure and arrhythmias, produced in

The most common are ventricular arrhythmias, caused by infiltration of granulomas in the ventricular myocardium causing a focus for abnormal automaticity, or a disruption of ventricular activation and recover [100]. In patients with cardiac sarcoidosis, ventricular arrhythimias and sudden death, due to ventricular tachycardia, are common causes of death. Ventricular tachycardia is one of the most common manifestations of cardiac involvement, being the 24-h ambulatory monitoring the best way to detect them. Supraventricular arrhyth‐

Caused by the granulomatous infiltration at the atrioventricular node or bundle of His leading to a first degree heart block. Initially, patients are usually asymptomatic but they can progress

Caused by extensive granulomatous infiltration of the myocardium. May cause impairment of systolic or diastolic function. Diagnostic is difficult and many patients with heart failure

to complete heart block [101].This can be detected by routine electrocardiography.

due to sarcoidosis disease are diagnostic of idiopathic dilated cardiomyopathy.

**5.1. Epidemiology**

20-30% of cases.


**Table 4.** Presenting symptoms in Sarcoidosis-associated pulmonary hypertension

#### **4.3. Diagnosis**

Patients with SAPH usually present with restrictive dysfunction on pulmonary function tests, and decrease in carbón monoxide diffusion capacity (DLCO) out of proportion to the decrease in total lung capacity (TLC). Forced vital capacity (FVC), forced expiratory volumen in 1 second (FEV1) and DLCO have been reported to be significantly lower in patients with Sarcoidosis and PH when compared with patients without PH [99].La hipoxemia esta frecuentemente presente en los pacientes con SAPH siendo este grupo uno de los que con probabilidad va a requerir oxigeno suplementario y por otra parte recorren menos metros en el 6-minute walking test cuando se comparan con pacientes que tienen Sarcoidosis en el mismo estadio radiológico pero sin PH [99].

Transthoracic echocardiography (TTE) represents a noninvasive screening method to evaluate the presence of PH in sarcoidosis. It is helpful to describe other potential cardiac abnormalities, such as left heart disease, presence of shunts or pericardial effusion, and to evaluate the right heart anatomically and functionally. Echocardiography may be used to estimate the right ventricular systolic pressure (RVSP) if a tricuspid regurgitation jet is present. Echocardio‐ graphically estimated RVSP had inadequate positive and negative predictive value in diag‐ nosing PH in advanced lung disease, so it´s a screening test that cannot supplant right heart cathetetization (RHC) for the SAPH diagnosis.

RHC is the diagnostic gold standard for SAPH. TTE was unable to detect RVSP in 30% of the patients and 24% of the patients with elevated PAP had a pulmonary capillary wedge pressure (PCWP) in excess of 20 mm Hg, underscoring the importance of left ventricular disease in the pathogenesis of PH in some Sarcoidosis patients. RHC should be per‐ formed in all cases in which SAPH is suspected or when echocardiography is suggestive of right heart pathology.

### **5. Cardiac sarcoidosis**

#### **5.1. Epidemiology**

Sudden death caused by compression of large pulmonary arteries, occlusion of the pulmonary veins by a sarcoid involvement intravascular or combination of SAPH and portal hypertension

Patients with SAPH usually present with restrictive dysfunction on pulmonary function tests, and decrease in carbón monoxide diffusion capacity (DLCO) out of proportion to the decrease in total lung capacity (TLC). Forced vital capacity (FVC), forced expiratory volumen in 1 second (FEV1) and DLCO have been reported to be significantly lower in patients with Sarcoidosis and PH when compared with patients without PH [99].La hipoxemia esta frecuentemente presente en los pacientes con SAPH siendo este grupo uno de los que con probabilidad va a requerir oxigeno suplementario y por otra parte recorren menos metros en el 6-minute walking test cuando se comparan con pacientes que tienen Sarcoidosis en el mismo estadio radiológico

Transthoracic echocardiography (TTE) represents a noninvasive screening method to evaluate the presence of PH in sarcoidosis. It is helpful to describe other potential cardiac abnormalities, such as left heart disease, presence of shunts or pericardial effusion, and to evaluate the right heart anatomically and functionally. Echocardiography may be used to estimate the right ventricular systolic pressure (RVSP) if a tricuspid regurgitation jet is present. Echocardio‐ graphically estimated RVSP had inadequate positive and negative predictive value in diag‐ nosing PH in advanced lung disease, so it´s a screening test that cannot supplant right heart

RHC is the diagnostic gold standard for SAPH. TTE was unable to detect RVSP in 30% of the patients and 24% of the patients with elevated PAP had a pulmonary capillary wedge pressure (PCWP) in excess of 20 mm Hg, underscoring the importance of left ventricular disease in the pathogenesis of PH in some Sarcoidosis patients. RHC should be per‐ formed in all cases in which SAPH is suspected or when echocardiography is suggestive

**Symptoms Frequency %**

*Dyspnea on exertion* 85

*Cough* 36

*Chest pain* 10

*Palpitations* 10

*Asymptomatic* 8

**Table 4.** Presenting symptoms in Sarcoidosis-associated pulmonary hypertension

is infrequent.

122 Sarcoidosis

**4.3. Diagnosis**

pero sin PH [99].

of right heart pathology.

cathetetization (RHC) for the SAPH diagnosis.

The presence of cardiac sarcoidosis is influenced by race. Over 25% of Japanese sarcoidosis patients present cardiac disease, only 5% of patients in the United States and Europe are affected at this level. Although clinical evidence of myocardial involvement is present in 5% of patients, there are autopsy studies that indicate that sublinical cardiac disease is present in 20-30% of cases.

### **5.2. Clinical manifestations**

Cardiac Sarcoidosis can be an incidental finding, has a benign course or being a life-threatening disorder. Clinicians should suspect this disease in young or middle-aged patients with cardiac symptoms and in any patients with a history of sarcoidosis who develop arrhythmias, conduction disturbances or other cardiac symptoms.

Clinical manifestations depend on the location and extent of granulomatous infiltration, being the most common cause of cardiac involvement secondary to infiltration of the myocardium. Usually, cardiac disease appears with any other organ involvement (lung, skin…). The most frequent manifestations of cardiac sarcoidosis are heart failure and arrhythmias, produced in both cases,by the infiltration of the myocardium.

#### **5.3. Cardiac arrhythmias**

The most common are ventricular arrhythmias, caused by infiltration of granulomas in the ventricular myocardium causing a focus for abnormal automaticity, or a disruption of ventricular activation and recover [100]. In patients with cardiac sarcoidosis, ventricular arrhythimias and sudden death, due to ventricular tachycardia, are common causes of death. Ventricular tachycardia is one of the most common manifestations of cardiac involvement, being the 24-h ambulatory monitoring the best way to detect them. Supraventricular arrhyth‐ mias are infrequent.

#### **5.4. Conduction abnormalities**

Caused by the granulomatous infiltration at the atrioventricular node or bundle of His leading to a first degree heart block. Initially, patients are usually asymptomatic but they can progress to complete heart block [101].This can be detected by routine electrocardiography.

#### **5.5. Heart failure**

Caused by extensive granulomatous infiltration of the myocardium. May cause impairment of systolic or diastolic function. Diagnostic is difficult and many patients with heart failure due to sarcoidosis disease are diagnostic of idiopathic dilated cardiomyopathy.

#### **5.6. Other clinical manifestations**

**a.** *Valvular dysfunction:* The most frequent is the involvement of the mitral valve caused by diastolic dysfunction and left ventricular dilatation or granulomatous involvement of the papillary muscle [102]. Less common is the tricuspid valve dysfunction.

20% prevalence in patients with neurosarcoidosis or 1% in those affected with sarcoidosis. The prevalence of neurosarcoidosis is similar to schizophrenia, between 0,50-1,46% of general population. Thus, a study shows that 2 of each 268 patients with a first schizophrenia episode,

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 125

Neurologic complications occur in approximately 5 percent of patients with sarcoidosis [108-112]. Neurosarcoidosis is a diagnostic consideration in patients with known sarcoidosis who develop neurologic complaints and in patients presenting de novo with a constellation of findings consistent with the disease [113, 114]. About 50 percent of patients with neurosar‐ coidosis present with neurologic difficulties at the time of the diagnosis. One-third of those with neurosarcoidosis has or develops more than one neurologic manifestation of their disease.

Any portion of the central or peripheral nervous system can be affected by sarcoidosis. Neuropsychiatric: seizures, amnesia, psychosis and disorientation. Cranial mononeuropathy. Peripheral facial nerve palsy develops in 25 to 50 percent of patients with neurosarcoidosis [111, 114, 115]. The facial nerve palsy can be unilateral or bilateral (simultaneous or sequential) and recurrent. Optic neuropathy and cranial nerve VIII dysfunction can lead to intermittent or progressive visual, auditory, or vestibular dysfunction. Neuroendocrine dysfunction typically occurs with hypothalamic inflammation, resulting in polyuria or disturbances in thirst, sleep, appetite, temperature, or libido. Hypothalamic or pituitary lesions may also cause thyroid, gonadal, or adrenal abnormalities [115, 117]. Polyuria can result from one or more factors in patients with sarcoidosis. Direct hypothalamic involvement can lead to central diabetes insipidus or primary polydipsia, while hyperkalemia (due to production of calcitriol by activated macrophages) can cause nephrogenic diabetes insipidus [117]. Thus, all patients with sarcoidosis and polyuria require a water restriction test to establish the correct diagnosis. Granulomatous inflammation in a perivascular distribution can involve the brain and produce partial or generalized seizures, or a restricted or generalized encephalopathy/vasculopathy [114, 115]. Patients can present with cognitive or behavioral problems and/or focal neurologic deficits referable to the anatomic area involved. In rare cases, this manifests as a focal cerebral infarction [118]. A myelopathy or radiculopathy can occur if granulomatous inflammation affects the spinal cord [114, 115, 119, 120]. The lesions are typically perivascular, they can be extra medullary or intramedullary, and can involve the caudal equine. Communicating or no communicating hydrocephalus may develop acutely or subacutely. Asymptomatic ventricular enlargement may be incidentally detected by imaging studies. Sudden death can rarely result from acute obstruction to CSF flow. Meningeal involvement can take the form of either acute aseptic meningitis or chronic meningitis. Meningeal mass lesions also can develop. Peripheral neuropathic presentations include a mononeuropathy, mononeuritis multiplex, and general‐ ized sensory, small fiber sensory, sensorimotor, autonomic and motor polyneuropathies [122]. The symptoms can be acute, subacute, or chronic; electromyography usually reveals an axonal neuropathy. In addition, an acute generalized demyelinating motor neuropathy similar to the Guillain-Barré syndrome also has been described [123]. Carpal tunnel syndrome appears to be more common among patients with sarcoidosis than the general population [124-126].

they had neurosarcoidosis.

**7.1. Clinical presentation**


### **6. Gastrointestinal and liver sarcoidosis**

#### **6.1. Liver disease**

Occurs in 13% of patients with systemic sarcoidosis [104]. Isolated liver involvement is infrequent. In most cases there are no symptoms but can appear hepatosplenomegaly, elevated liver enzymes, cholestasis or portal hypertension. In addition, 60% of patients with liver disease have fever and / or concomitant arthralgia [104].

Although in most cases the granulomas in the liver are small and are located in the portal space, symptoms consistent with chronic cholestasis [105] portal hypertension or Bud-Chiari syndrome can appear [106] Intrahepatic cholestasis can resemble primary biliary cirrhosis or sclerosing cholangitis.

Usually liver function is normal, but the most common abnormality is an elevation of alkaline phosphatase level.

#### **6.2. Gastrointestinal involvement**

Affects less than 1% of patients with sarcoidosis, being the stomach the most affected organ of the digestive tract. The symptoms of patients with gastric involvement are inespecific: epigastric pain, heartburn, abdominal discomfort, nausea or vomiting, diarrhea and significant weight loss.

Involvement of the intestine is very infrequent and can occasionally coexist with Crohn's disease [107].

### **7. Neurosarcoidosis**

Neurosarcoidosis is the neurologic manifestation of sarcoidosis, a system granulomatous disease. The most affected organ is the lung, but it can also affect eyes, liver and nervous system. It affects the 5-15% of patients with sarcoidosis. It can be manifested by a wide variety of symptoms: peripheral neuropathy, central symptoms, loss of memory and behavior changes. Psiquiatric manifestations include, but not exclusively, psychosis and delirium, with 20% prevalence in patients with neurosarcoidosis or 1% in those affected with sarcoidosis. The prevalence of neurosarcoidosis is similar to schizophrenia, between 0,50-1,46% of general population. Thus, a study shows that 2 of each 268 patients with a first schizophrenia episode, they had neurosarcoidosis.

Neurologic complications occur in approximately 5 percent of patients with sarcoidosis [108-112]. Neurosarcoidosis is a diagnostic consideration in patients with known sarcoidosis who develop neurologic complaints and in patients presenting de novo with a constellation of findings consistent with the disease [113, 114]. About 50 percent of patients with neurosar‐ coidosis present with neurologic difficulties at the time of the diagnosis. One-third of those with neurosarcoidosis has or develops more than one neurologic manifestation of their disease.

#### **7.1. Clinical presentation**

**5.6. Other clinical manifestations**

**6.1. Liver disease**

124 Sarcoidosis

sclerosing cholangitis.

**6.2. Gastrointestinal involvement**

phosphatase level.

weight loss.

disease [107].

**7. Neurosarcoidosis**

abdominal aorta aneurysm [103].

**6. Gastrointestinal and liver sarcoidosis**

disease have fever and / or concomitant arthralgia [104].

**a.** *Valvular dysfunction:* The most frequent is the involvement of the mitral valve caused by diastolic dysfunction and left ventricular dilatation or granulomatous involvement of the

**b.** Aorta aneurysm: Although are infrequent, has been described descending thoracic and

Occurs in 13% of patients with systemic sarcoidosis [104]. Isolated liver involvement is infrequent. In most cases there are no symptoms but can appear hepatosplenomegaly, elevated liver enzymes, cholestasis or portal hypertension. In addition, 60% of patients with liver

Although in most cases the granulomas in the liver are small and are located in the portal space, symptoms consistent with chronic cholestasis [105] portal hypertension or Bud-Chiari syndrome can appear [106] Intrahepatic cholestasis can resemble primary biliary cirrhosis or

Usually liver function is normal, but the most common abnormality is an elevation of alkaline

Affects less than 1% of patients with sarcoidosis, being the stomach the most affected organ of the digestive tract. The symptoms of patients with gastric involvement are inespecific: epigastric pain, heartburn, abdominal discomfort, nausea or vomiting, diarrhea and significant

Involvement of the intestine is very infrequent and can occasionally coexist with Crohn's

Neurosarcoidosis is the neurologic manifestation of sarcoidosis, a system granulomatous disease. The most affected organ is the lung, but it can also affect eyes, liver and nervous system. It affects the 5-15% of patients with sarcoidosis. It can be manifested by a wide variety of symptoms: peripheral neuropathy, central symptoms, loss of memory and behavior changes. Psiquiatric manifestations include, but not exclusively, psychosis and delirium, with

papillary muscle [102]. Less common is the tricuspid valve dysfunction.

**c.** Cor pulmonale: May occur secondary to pulmonary fibrosis.

Any portion of the central or peripheral nervous system can be affected by sarcoidosis. Neuropsychiatric: seizures, amnesia, psychosis and disorientation. Cranial mononeuropathy. Peripheral facial nerve palsy develops in 25 to 50 percent of patients with neurosarcoidosis [111, 114, 115]. The facial nerve palsy can be unilateral or bilateral (simultaneous or sequential) and recurrent. Optic neuropathy and cranial nerve VIII dysfunction can lead to intermittent or progressive visual, auditory, or vestibular dysfunction. Neuroendocrine dysfunction typically occurs with hypothalamic inflammation, resulting in polyuria or disturbances in thirst, sleep, appetite, temperature, or libido. Hypothalamic or pituitary lesions may also cause thyroid, gonadal, or adrenal abnormalities [115, 117]. Polyuria can result from one or more factors in patients with sarcoidosis. Direct hypothalamic involvement can lead to central diabetes insipidus or primary polydipsia, while hyperkalemia (due to production of calcitriol by activated macrophages) can cause nephrogenic diabetes insipidus [117]. Thus, all patients with sarcoidosis and polyuria require a water restriction test to establish the correct diagnosis. Granulomatous inflammation in a perivascular distribution can involve the brain and produce partial or generalized seizures, or a restricted or generalized encephalopathy/vasculopathy [114, 115]. Patients can present with cognitive or behavioral problems and/or focal neurologic deficits referable to the anatomic area involved. In rare cases, this manifests as a focal cerebral infarction [118]. A myelopathy or radiculopathy can occur if granulomatous inflammation affects the spinal cord [114, 115, 119, 120]. The lesions are typically perivascular, they can be extra medullary or intramedullary, and can involve the caudal equine. Communicating or no communicating hydrocephalus may develop acutely or subacutely. Asymptomatic ventricular enlargement may be incidentally detected by imaging studies. Sudden death can rarely result from acute obstruction to CSF flow. Meningeal involvement can take the form of either acute aseptic meningitis or chronic meningitis. Meningeal mass lesions also can develop. Peripheral neuropathic presentations include a mononeuropathy, mononeuritis multiplex, and general‐ ized sensory, small fiber sensory, sensorimotor, autonomic and motor polyneuropathies [122]. The symptoms can be acute, subacute, or chronic; electromyography usually reveals an axonal neuropathy. In addition, an acute generalized demyelinating motor neuropathy similar to the Guillain-Barré syndrome also has been described [123]. Carpal tunnel syndrome appears to be more common among patients with sarcoidosis than the general population [124-126]. Muscle involvement includes asymptomatic microscopic nodules, isolated palpable nodules, an acute or chronic proximal myopathy, and muscle atrophy [127].

**1.** Ophthalmologic examination

sarcoidosis [114, 115].

might be amenable to biopsy

**b.** Neurodiagnostic testing:

appropriate clinical setting [128].

matter lesions on MRI [128].

**d.** Lumbar puncture:

**c.** Neuroimaging:

**2.** Endoscopic nasal and sinus examination. A chest x-ray or computed tomographic scan of the chest to look for hilar adenopathy or parenchymal changes consistent with pulmonary sarcoidosis. Positive findings suggestive of sarcoidosis on chest imaging have been reported in 24 to 68 percent of individuals who present with neurologic

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 127

**3.** Serum angiotensin converting enzyme (ACE) assay, which may be helpful if elevated; however, an elevated serum ACE is not specific for sarcoidosis, and the ACE concentration

**4.** In occasional cases, a magnetic resonance, gallium, or fluorodeoxyglucose positron emission tomographic scan, may highlight otherwise occult areas of inflammation that

Neurologic evaluation should proceed if no extra neural tissue is available for biopsy. Unfortunately, no neurodiagnostic tests are pathognomonic for neurosarcoidosis. However, neurodiagnostic tests help define the extent of disease and eliminate other diagnostic consid‐ erations, particularly infection and malignancy. Furthermore, a presumptive diagnosis of neurosarcoidosis is often made on the basis of MRI and lumbar puncture results in the

The imaging procedure of choice for CNS disease is contrast-enhanced MRI [115, 116, 129]. Meningeal or parenchymal enhancement suggests active inflammation with disruption of the blood brain barrier, and parenchymal or meningeal masses and hydrocephalus are easily identified. Involvement of the optic nerve or other cranial nerves can be documented, and spinal cord and cauda equine inflammation is well seen on targeted images. Multiple paren‐ chymal nodules may actually represent inflammation extending along the Virchow-Robin spaces deep into the brain or spinal cord. In one series of 29 patients with neurosarcoidosis, approximately 40 percent demonstrated meningeal enhancement and/or multiple white

Cerebrospinal fluid (CSF) abnormalities occur frequently in patients with CNS sarcoidosis [114, 115]: The CSF opening pressure is elevated in approximately 10 percent of patients, and the total protein is increased in two-thirds of patients, typically up to 250 mg/dL. A pleocytosis is present in approximately 50 percent of patients. Glucose can be normal or low, as can be seen in CNS infections or carcinomatous meningitis. A predominantly mononuclear cell pleocytosis is common. The IgG index can be elevated, and oligoclonal bands may be present.

The CSF ACE concentration is occasionally elevated, but reliable normal values are lacking

and CSF ACE may also be increased with infection or carcinomatous meningitis.

may not necessarily be elevated if the patient has isolated neurosarcoidosis

In some series of patients affected with intracranial hypertension syndrome, whose manifes‐ tation is headache, the diagnosis is neurosarcoidosis. It is uncommon, however, it must be include in differential diagnosis [109].

Patients presenting with neurosarcoidosis may have no systemic features of the disease. In one case series, non-neurologic symptoms were present in less than one-fourth of patients and were most commonly anterior uveitis, cough and dyspnea, renal impairment, rash, and polyarthritis [114].

#### **7.2. Diagnosis**

Neurosarcoidosis is a diagnostic consideration in patients with known sarcoidosis who develop neurologic findings, although an intercurrent infection or malignancy must be excluded. Patients who develop a neurologic illness consistent with neurosarcoidosis but are not known to have sarcoidosis present a diagnostic challenge. Table 5 summarizes findings in patients with Neurosarcoidosis.


**Table 5.** Findings in patients with Neurosarcoidosis

#### **a.** Clinical evaluation:

If neurosarcoidosis is suspected, the patient should be evaluated for evidence of extra neural disease because obtaining nerve tissue for diagnostic evaluation is often difficult. Corticoste‐ roids can eliminate evidence of systemic inflammation, and the diagnostic evaluation should be pursued in a rapid fashion while withholding immunosuppressive therapy unless severe illness mandates its use.

The search for extra neural sarcoidosis should include a thorough evaluation of the skin, lymph nodes, and lungs. Other tests that may be useful are:

**1.** Ophthalmologic examination

Muscle involvement includes asymptomatic microscopic nodules, isolated palpable nodules,

In some series of patients affected with intracranial hypertension syndrome, whose manifes‐ tation is headache, the diagnosis is neurosarcoidosis. It is uncommon, however, it must be

Patients presenting with neurosarcoidosis may have no systemic features of the disease. In one case series, non-neurologic symptoms were present in less than one-fourth of patients and were most commonly anterior uveitis, cough and dyspnea, renal impairment, rash, and

Neurosarcoidosis is a diagnostic consideration in patients with known sarcoidosis who develop neurologic findings, although an intercurrent infection or malignancy must be excluded. Patients who develop a neurologic illness consistent with neurosarcoidosis but are not known to have sarcoidosis present a diagnostic challenge. Table 5 summarizes findings in

If neurosarcoidosis is suspected, the patient should be evaluated for evidence of extra neural disease because obtaining nerve tissue for diagnostic evaluation is often difficult. Corticoste‐ roids can eliminate evidence of systemic inflammation, and the diagnostic evaluation should be pursued in a rapid fashion while withholding immunosuppressive therapy unless severe

The search for extra neural sarcoidosis should include a thorough evaluation of the skin, lymph

an acute or chronic proximal myopathy, and muscle atrophy [127].

**Findings in patients with Neurosarcoidosis Frequency (%)**

**Findings in Cerebrospinal fluid Frequency (%)**

Elevated total protein 66% Pleocytosis 50% Elevated openning pressure 10%

Findings in Chest Rx 24-68% Cranial mononeuropathy 25-50% MRI meningeal enhancement 40% Psychiatric symptoms 20%

include in differential diagnosis [109].

patients with Neurosarcoidosis.

**Table 5.** Findings in patients with Neurosarcoidosis

nodes, and lungs. Other tests that may be useful are:

**a.** Clinical evaluation:

illness mandates its use.

polyarthritis [114].

**7.2. Diagnosis**

126 Sarcoidosis


Neurologic evaluation should proceed if no extra neural tissue is available for biopsy. Unfortunately, no neurodiagnostic tests are pathognomonic for neurosarcoidosis. However, neurodiagnostic tests help define the extent of disease and eliminate other diagnostic consid‐ erations, particularly infection and malignancy. Furthermore, a presumptive diagnosis of neurosarcoidosis is often made on the basis of MRI and lumbar puncture results in the appropriate clinical setting [128].

**c.** Neuroimaging:

The imaging procedure of choice for CNS disease is contrast-enhanced MRI [115, 116, 129]. Meningeal or parenchymal enhancement suggests active inflammation with disruption of the blood brain barrier, and parenchymal or meningeal masses and hydrocephalus are easily identified. Involvement of the optic nerve or other cranial nerves can be documented, and spinal cord and cauda equine inflammation is well seen on targeted images. Multiple paren‐ chymal nodules may actually represent inflammation extending along the Virchow-Robin spaces deep into the brain or spinal cord. In one series of 29 patients with neurosarcoidosis, approximately 40 percent demonstrated meningeal enhancement and/or multiple white matter lesions on MRI [128].

**d.** Lumbar puncture:

Cerebrospinal fluid (CSF) abnormalities occur frequently in patients with CNS sarcoidosis [114, 115]: The CSF opening pressure is elevated in approximately 10 percent of patients, and the total protein is increased in two-thirds of patients, typically up to 250 mg/dL. A pleocytosis is present in approximately 50 percent of patients. Glucose can be normal or low, as can be seen in CNS infections or carcinomatous meningitis. A predominantly mononuclear cell pleocytosis is common. The IgG index can be elevated, and oligoclonal bands may be present.

The CSF ACE concentration is occasionally elevated, but reliable normal values are lacking and CSF ACE may also be increased with infection or carcinomatous meningitis.

Caution should be applied in performing a LP in patients with neurosarcoidosis if there is evidence of increased intracranial pressure. A funduscopic examination to exclude papillede‐ ma and an MRI to exclude ventricular enlargement, cerebral edema, and a mass lesion should precede LP [130].

folds. Upon resolution, faintly discolored, occasionally atrophic macules may remain at

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 129

Nodular sarcoidosis is a relatively common form of cutaneous sarcoidosis that results from large collections of sarcoidal granulomas in the dermis or subcutaneous tissue [135]. Nodules tend to be between 1 and 2 cm in diameter and may be single or multiple. On the nose, nodular

Characteristically, lesions are asymptomatic or pruritic, and consist of slightly infiltrated, slightly hyperpigmented patches studded with slightly raised papules that are often around 1 mm in diameter [136]. Facial skin, especially the periorifial or eyelid area, is the most common

Presents with oval or annular, indurated, discrete plaques that are flesh – colored, erythema‐ tous, or brown. Frequent site of involvement include the shoulders and arms, back, and

Lupus pernio is characterized by violaceous or erythematous indured papules, plaques, or nodules that are primarily distributed on the central face [138]. The alar rim of the nose is often affected. Lupus pernio is more common in women than in men and is associated with chronic disease and extrapulmonary involvement [138, 139]. Without treatment, the lesions progres‐ sively increase in thickness, size, and induration, eventually resulting in considerable cosmetic

The presence of lupus pernio appears to be associated with an increased risk for extra cutaneous disease, particularly sarcoidosis involving the respiratory tract [140]. When severe, granulomatous inflammation of the upper respiratory tract can result in airway

Erythema nodosum develops in up to 25 percent of patients with sarcoidosis and is clinically and histologically identical to erythema nodosum secondary to other causes. García Porrúa et al in Spanish study of 106 biopsy proven cases of erythema nodosum, 20 percent of patients had sarcoidosis [142]. Arthritis, lower extremity edema, and low grave fever are the most

The clinical feature of subcutaneous sarcoidosis can resemble erythema nodosum. Biopsy is useful for distinguishing between these disorders. Biopsy specimens of erythema nodosum

common systemic symptoms associated with erythema nodosum.

previous sites of involvement [135, 136].

sarcoidosis can resemble rhinophyma [135, 137]-

**b.** Nodular sarcoidosis

**c.** Maculopapular sarcoidosis

site of involvement.

buttocks [131].

disfigurement.

obstruction [141].

**8.2. Non-Specific eruptions**

**a.** Erythema nodosum

**e.** Lupus pernio

**d.** Plaque sarcoidosis

**e.** Other tests:

Other diagnostic tests, such as electroencephalography, evoked potentials, and angiography, are occasionally indicated to exclude other conditions. Nerve conduction studies (NCS) and electromyography (EMG) can help localize neuromuscular lesions, depending on the clinical syndrome.

Although false-positive reactions to the Kveim-Siltzbach test are reported to be rare; the test has limited utility [114]. The test is not standardized; it is not universally available; and there are concerns regarding the transmission of HIV and hepatitis.

**f.** Biopsy:

If the diagnosis remains in doubt, meningeal, brain, or spinal cord biopsy is occasionally indicated. Extra neural tissue biopsy from other clinically affected organs is generally pref‐ erable when possible, as it is less risky; skin, lymph node, and lung (trans bronchial) biopsies can be of high yield [114, 115]. Muscle and peripheral nerve biopsy, including an epidermal biopsy with quantitative nerve terminal analysis to document small fiber sensory neuropathy, can all be easily performed for the appropriate syndrome.

### **8. Cutaneous manifestations of sarcoidosis**

Cutaneous lesions of sarcoidosis may present with variety of morphologies [131]. Although not life-threatening, the unsightly skin lesions of sarcoidosis can be emotionally devastating [132]. Given the wide variability of clinical manifestations, it is one of the "great imitators," making it necessary to consider clinical, epidemiological, radiographic, laboratory, and histopathological criteria to make the diagnosis [133]

Skin involvement is common (occurring in 25 to 35 % of patients with sarcoidosis). Cutaneous manifestation of sarcoidosis could be one of the two following: specific lesions, which dem‐ onstrate granuloma on biopsy; and nonspecific lesions that do not have granulomas but are inflammatory reactions [134].

Specific lesions are estimated to occur in 9 to 15 percent of patients with sarcoidosis. Although their histopathologic features are similar, the clinical manifestations of specific lesions vary widely [135]. Papules, nodules, plaques, and infiltrated scars are among the most common presentations; other manifestations also occur.

#### **8.1. Specific eruptions**

**a.** Papular sarcoidosis

Papular sarcoidosis is a common specific cutaneous manifestation of sarcoidosis. Papular sarcoidosis most frequently occurs on the face, with predilection for the eyelids and nasolabial folds. Upon resolution, faintly discolored, occasionally atrophic macules may remain at previous sites of involvement [135, 136].

**b.** Nodular sarcoidosis

Caution should be applied in performing a LP in patients with neurosarcoidosis if there is evidence of increased intracranial pressure. A funduscopic examination to exclude papillede‐ ma and an MRI to exclude ventricular enlargement, cerebral edema, and a mass lesion should

Other diagnostic tests, such as electroencephalography, evoked potentials, and angiography, are occasionally indicated to exclude other conditions. Nerve conduction studies (NCS) and electromyography (EMG) can help localize neuromuscular lesions, depending on the clinical

Although false-positive reactions to the Kveim-Siltzbach test are reported to be rare; the test has limited utility [114]. The test is not standardized; it is not universally available; and there

If the diagnosis remains in doubt, meningeal, brain, or spinal cord biopsy is occasionally indicated. Extra neural tissue biopsy from other clinically affected organs is generally pref‐ erable when possible, as it is less risky; skin, lymph node, and lung (trans bronchial) biopsies can be of high yield [114, 115]. Muscle and peripheral nerve biopsy, including an epidermal biopsy with quantitative nerve terminal analysis to document small fiber sensory neuropathy,

Cutaneous lesions of sarcoidosis may present with variety of morphologies [131]. Although not life-threatening, the unsightly skin lesions of sarcoidosis can be emotionally devastating [132]. Given the wide variability of clinical manifestations, it is one of the "great imitators," making it necessary to consider clinical, epidemiological, radiographic, laboratory, and

Skin involvement is common (occurring in 25 to 35 % of patients with sarcoidosis). Cutaneous manifestation of sarcoidosis could be one of the two following: specific lesions, which dem‐ onstrate granuloma on biopsy; and nonspecific lesions that do not have granulomas but are

Specific lesions are estimated to occur in 9 to 15 percent of patients with sarcoidosis. Although their histopathologic features are similar, the clinical manifestations of specific lesions vary widely [135]. Papules, nodules, plaques, and infiltrated scars are among the most common

Papular sarcoidosis is a common specific cutaneous manifestation of sarcoidosis. Papular sarcoidosis most frequently occurs on the face, with predilection for the eyelids and nasolabial

are concerns regarding the transmission of HIV and hepatitis.

can all be easily performed for the appropriate syndrome.

**8. Cutaneous manifestations of sarcoidosis**

histopathological criteria to make the diagnosis [133]

presentations; other manifestations also occur.

inflammatory reactions [134].

**8.1. Specific eruptions a.** Papular sarcoidosis

precede LP [130]. **e.** Other tests:

128 Sarcoidosis

syndrome.

**f.** Biopsy:

Nodular sarcoidosis is a relatively common form of cutaneous sarcoidosis that results from large collections of sarcoidal granulomas in the dermis or subcutaneous tissue [135]. Nodules tend to be between 1 and 2 cm in diameter and may be single or multiple. On the nose, nodular sarcoidosis can resemble rhinophyma [135, 137]-

**c.** Maculopapular sarcoidosis

Characteristically, lesions are asymptomatic or pruritic, and consist of slightly infiltrated, slightly hyperpigmented patches studded with slightly raised papules that are often around 1 mm in diameter [136]. Facial skin, especially the periorifial or eyelid area, is the most common site of involvement.

#### **d.** Plaque sarcoidosis

Presents with oval or annular, indurated, discrete plaques that are flesh – colored, erythema‐ tous, or brown. Frequent site of involvement include the shoulders and arms, back, and buttocks [131].

#### **e.** Lupus pernio

Lupus pernio is characterized by violaceous or erythematous indured papules, plaques, or nodules that are primarily distributed on the central face [138]. The alar rim of the nose is often affected. Lupus pernio is more common in women than in men and is associated with chronic disease and extrapulmonary involvement [138, 139]. Without treatment, the lesions progres‐ sively increase in thickness, size, and induration, eventually resulting in considerable cosmetic disfigurement.

The presence of lupus pernio appears to be associated with an increased risk for extra cutaneous disease, particularly sarcoidosis involving the respiratory tract [140]. When severe, granulomatous inflammation of the upper respiratory tract can result in airway obstruction [141].

#### **8.2. Non-Specific eruptions**

#### **a.** Erythema nodosum

Erythema nodosum develops in up to 25 percent of patients with sarcoidosis and is clinically and histologically identical to erythema nodosum secondary to other causes. García Porrúa et al in Spanish study of 106 biopsy proven cases of erythema nodosum, 20 percent of patients had sarcoidosis [142]. Arthritis, lower extremity edema, and low grave fever are the most common systemic symptoms associated with erythema nodosum.

The clinical feature of subcutaneous sarcoidosis can resemble erythema nodosum. Biopsy is useful for distinguishing between these disorders. Biopsy specimens of erythema nodosum lesions show nonspecific septal panniculitis, which neither confirms nor negates the diagnosis of sarcoidosis [143].

**9.1. Acute arthritis**

uveitis and arthritis [151].

**9.2. Chronic arthritis**

of granulomas.

**9.3. Diagnosis**

**9.4. Treatment**

based upon clinical features alone [132].

Acute sarcoid arthritis may present in isolation or as part of Lofgren's syndrome (association of arthritis, erythema nodosum and bilateral hilar lymphadenopathy). Joint effusion is discrete [149]. Rheumatoid factor and ANA may be positive, as in the general sarcoidosis [146]. The acute polyarthritis most commonly involves ankles (>90 percent), often bilaterally, followed by other larger joints of lower extremity and may be mistaken for a reactive arthritis. The arthritis is mostly oligoarticular (87%), and involvement is typically symmetrical (76%). Glennas et al, in a prospective study of 189 patients presenting with symptoms suggestive of reactive arthritis, 17 (9%) were eventually diagnosed with acute sarcoid arthritis. Ten had

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 131

**Löfgren´s syndrome:** The triad of hilar adenopathy, acute polyarthritis and erythema nodo‐ sum characterizes Löfgren´s syndrome. Löfgren´s syndrome is usually self-limiting. Erythema nodosum typically disappears in a few months [144]. Approximately one third of patients have persistent arthritis; rarely, the arthritis symptoms are recurrent. Hilar adenopathy tends to resolve over time up to 90 percent of patients. Erythema nodosum is more often seen in female

Sarcoid arthritis can resemble rheumatic fever when the polyarthritis is migratory. It may resemble patients with juvenile idiopathic arthritis in young children presenting with both

Patients presenting with chronic arthritis are typically older than patients with acute arthritis or Löfgren´s syndrome [144]. The ankle, knees, hands, wrist, metacarpophalangeal and proximal interphalangeal joint are the joints most frequently involved; rarely, the sacroiliac and temporomandibular joints may also be affected [144]. Chronic arthritis is frequently associated with parenchymal lung disease and other extrapulmonary manifestations [144]. The correlation between extremely high serum of angiotensin converting enzyme levels and extrathoracic sarcoidosis, including chronic arthritis, probably reflects the high total body load

Diagnosis of sarcoid arthropathy is based upon suggestive clinical, imaging, synovial fluid, and, in selected cases, synovial tissue biopsy. Classic Löfgren´s syndrome can be diagnosed

Sarcoid arthritis should be treated with nonsteroidal antiinflammatory agents. Corticosteroids and other immunosuppressive drugs as colchicine and hydroxychloroquine should be reserved for refractory cases. Biological therapies such as the anti-TNFa and the anti-CD20 were showed to be effective in some case reports of severe and refractory disease [152].

Löfgren´s syndrome, and 17 had bilateral ankle involvement [150].

compared with male patients presenting with Löfgren´s syndrome [142].

**b.** Löfgren´s syndrome

Löfgren´s syndrome is an acute presentation of sarcoidosis characterized by the triad of hilar adenopathy, erythema nodosum, and polyarthralgia or arthritis, with or without parenchymal infiltrates or fever [132, 144]. The presence of bilateral hilar adenopathy and erythema nodosum is usually, but no always, caused by acute sarcoidosis. More recently, the definition has been expanded to include patients with hilar adenopathy and periarticular inflammation with or without erythema nodosum [145].

#### **8.3. Management of cutaneous sarcoidosis**

**a.** First line agents:

Formal studies of local therapies for cutaneous sarcoidosis are limited, and the widespread use of topical and intralesional corticosteroids for this disease primarily are based upon clinical experience.

**Topical corticosteroids:** Superpotent topical corticosteroids are widely used for the treatment of cutaneous sarcoidosis: Clobetasol, halobetasol.

**Intralesional Corticosteroids:** Generally accepted that intralesional injection of corticosteroids can lead to flattening or resolution of cutaneous lesions: Triamcinolone

**b.** Seconds line agents

Systematic glucocorticoids (prednisone 20 to 40 mg/day)

Antimalarials: Hydroxychoroquine and chloroquine.

Methotrexate (10 to 25mg/week)

**c.** Refractory disease:

Patients who fail to respond to conventional first – and second – line therapies may benefit from treatment with infliximab or thalidomide.

### **9. Sarcoid arthropathy**

Arthritis is the most common musculoskeletal manifestation in sarcoidosis [146]. Approxi‐ mately 25 percent of patients with sarcoidosis have an associated arthropathy [147]. Real incidence is unclear since the diagnosis may be difficult when a patient presents with articular complaints alone; in this setting, the presence of sarcoidosis is established only after more commonly involved organs, such as the eye or lung, become affected [148].

#### **9.1. Acute arthritis**

lesions show nonspecific septal panniculitis, which neither confirms nor negates the diagnosis

Löfgren´s syndrome is an acute presentation of sarcoidosis characterized by the triad of hilar adenopathy, erythema nodosum, and polyarthralgia or arthritis, with or without parenchymal infiltrates or fever [132, 144]. The presence of bilateral hilar adenopathy and erythema nodosum is usually, but no always, caused by acute sarcoidosis. More recently, the definition has been expanded to include patients with hilar adenopathy and periarticular inflammation

Formal studies of local therapies for cutaneous sarcoidosis are limited, and the widespread use of topical and intralesional corticosteroids for this disease primarily are based upon clinical

**Topical corticosteroids:** Superpotent topical corticosteroids are widely used for the treatment

**Intralesional Corticosteroids:** Generally accepted that intralesional injection of corticosteroids

Patients who fail to respond to conventional first – and second – line therapies may benefit

Arthritis is the most common musculoskeletal manifestation in sarcoidosis [146]. Approxi‐ mately 25 percent of patients with sarcoidosis have an associated arthropathy [147]. Real incidence is unclear since the diagnosis may be difficult when a patient presents with articular complaints alone; in this setting, the presence of sarcoidosis is established only after more

commonly involved organs, such as the eye or lung, become affected [148].

can lead to flattening or resolution of cutaneous lesions: Triamcinolone

of sarcoidosis [143].

130 Sarcoidosis

**a.** First line agents:

**b.** Seconds line agents

**c.** Refractory disease:

**9. Sarcoid arthropathy**

Methotrexate (10 to 25mg/week)

experience.

**b.** Löfgren´s syndrome

with or without erythema nodosum [145].

**8.3. Management of cutaneous sarcoidosis**

of cutaneous sarcoidosis: Clobetasol, halobetasol.

Systematic glucocorticoids (prednisone 20 to 40 mg/day)

Antimalarials: Hydroxychoroquine and chloroquine.

from treatment with infliximab or thalidomide.

Acute sarcoid arthritis may present in isolation or as part of Lofgren's syndrome (association of arthritis, erythema nodosum and bilateral hilar lymphadenopathy). Joint effusion is discrete [149]. Rheumatoid factor and ANA may be positive, as in the general sarcoidosis [146]. The acute polyarthritis most commonly involves ankles (>90 percent), often bilaterally, followed by other larger joints of lower extremity and may be mistaken for a reactive arthritis. The arthritis is mostly oligoarticular (87%), and involvement is typically symmetrical (76%). Glennas et al, in a prospective study of 189 patients presenting with symptoms suggestive of reactive arthritis, 17 (9%) were eventually diagnosed with acute sarcoid arthritis. Ten had Löfgren´s syndrome, and 17 had bilateral ankle involvement [150].

**Löfgren´s syndrome:** The triad of hilar adenopathy, acute polyarthritis and erythema nodo‐ sum characterizes Löfgren´s syndrome. Löfgren´s syndrome is usually self-limiting. Erythema nodosum typically disappears in a few months [144]. Approximately one third of patients have persistent arthritis; rarely, the arthritis symptoms are recurrent. Hilar adenopathy tends to resolve over time up to 90 percent of patients. Erythema nodosum is more often seen in female compared with male patients presenting with Löfgren´s syndrome [142].

Sarcoid arthritis can resemble rheumatic fever when the polyarthritis is migratory. It may resemble patients with juvenile idiopathic arthritis in young children presenting with both uveitis and arthritis [151].

#### **9.2. Chronic arthritis**

Patients presenting with chronic arthritis are typically older than patients with acute arthritis or Löfgren´s syndrome [144]. The ankle, knees, hands, wrist, metacarpophalangeal and proximal interphalangeal joint are the joints most frequently involved; rarely, the sacroiliac and temporomandibular joints may also be affected [144]. Chronic arthritis is frequently associated with parenchymal lung disease and other extrapulmonary manifestations [144].

The correlation between extremely high serum of angiotensin converting enzyme levels and extrathoracic sarcoidosis, including chronic arthritis, probably reflects the high total body load of granulomas.

#### **9.3. Diagnosis**

Diagnosis of sarcoid arthropathy is based upon suggestive clinical, imaging, synovial fluid, and, in selected cases, synovial tissue biopsy. Classic Löfgren´s syndrome can be diagnosed based upon clinical features alone [132].

#### **9.4. Treatment**

Sarcoid arthritis should be treated with nonsteroidal antiinflammatory agents. Corticosteroids and other immunosuppressive drugs as colchicine and hydroxychloroquine should be reserved for refractory cases. Biological therapies such as the anti-TNFa and the anti-CD20 were showed to be effective in some case reports of severe and refractory disease [152].

### **10. Ocular manifestations in sarcoidosis**

The eye or adnexa are affected in 25 to 80% of the sarcoidosis patients. The disease can involve the orbit, lacrimal gland, anterior and posterior segments of the eye [153].

of symptoms. Systemic steroids can be used if uveitis does not resolve with topical therapy or for cases where vision loss is possible. Alternative agents include tacrolimus, methotrexate,

Clinical Manifestations of Sarcoidosis http://dx.doi.org/10.5772/55556 133

Minocycline may be an option for patients with comorbidities that make steroids a less

Interferon-alpha is commonly used to treat hepatitis C viral infection and has been reported to induce sarcoidosis and more recently ocular sarcoidosis with granulomatous panuveitis

In these cases topical steroids were used to treat ocular uveitis with systemic steroids for

Pneumologist, Medical-Surgical Unit of Respiratory Diseases. University Hospital Virgen

[1] Polychronopoulos VS, Prakash UB. Airway involvement in sarcoidosis. Chest 2009;

[2] James JC, Simpson CB. Treatment of laryngeal sarcoidosis with CO2 laser and mito‐

[3] Fouty BW, Pomeranz M, Thigpen TP, Martin RJ. Dilatation of bronchial stenoses due to sarcoidosis using a flexible fiberoptic bronchoscope. Chest 1994; 106:677.

[4] Baughman RP, Lower EE, Tami T. Upper airway. 4: Sarcoidosis of the upper respira‐

[5] Reed J, deShazo RD, Houle TT, et al. Clinical features of sarcoid rhinosinusitis. Am J

[6] Aubart FC, Ouayoun M, Brauner M, et al. Sinonasal involvement in sarcoidosis: a

[7] Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sar‐ coidosis: American Thoracic Society/European Respiratory Society/World Associa‐

case-control study of 20 patients. Medicine (Baltimore) 2006; 85:365.

Luis Jara-Palomares, Candela Caballero-Eraso, Cesar Gutiérrez, Alvaro Donate and

\*Address all correspondence to: luisoneumo@hotmail.com

mycin-C. Otolaryngol Head Neck Surg 2004; 130:262.

tory tract (SURT). Thorax 2010; 65:181.

and photodynamic therapy [157].

appealing option [158].

systemic findings.

**Author details**

with choroidal granulomas.

Jose Antonio Rodríguez-Portal

del Rocio. Seville, Spain

136:1371.

Med 2010; 123:856.

**References**

The disease can involve the orbit, lacrimal gland, anterior and posterior segments of the eye. Anterior uveitis is the most common manifestation, occurring in 65% of patients with ophthalmologic involvement [132]. Inflammation can affect the uveal tract leading to glaucoma, cataracts, and blindness. Typical sarcoid uveitis presents with bilateral muttonfat keratic precipitates, cells, flare, iris nodules, anterior and posterior synechia, and increased ocular pressure. Posterior involvement includes vitreitis, vasculitis, choroidal lesions, and optic neuropathy. Long-term complications are common, and cystoid macu‐ lar edema is the most important and sight-threatening consequence [153]. Acute uveitis presents with eye redness, cloudy vision, photophobia, and watering or can present asymptomatically (with a "quiet eye").

The gold standard for the diagnosis of sarcoidosis should be obtained with histologic exami‐ nation. However, an international workshop has recently established diagnostic criteria of "intraocular sarcoidosis" (sarcoidosis uveitis) on the basis of a combination of suggestive ophthalmological findings and laboratory tests, when biopsy is not performed or is negative. More recent techniques such as PET-scan and endoscopic ultrasound-guided fine-needle biopsy of intrathoracic nodes should be assessed in future prospective studies [154].

Chronic anterior uveitis, with insidious symptoms leading to glaucoma and vision loss, is more common than acute anterior uveitis. In about 10 to 15% of patients with uveitis, both the anterior and posterior segments are involved.

Lacrimal gland enlargement can cause dry eyes. Conjunctival follicles, dacryoscystitis, keratoconjunctivitis sicca, and retinal vasculitis also occur. Optic neuritis is an ophthalmo‐ logic emergency that requires immediate systemic therapy as it can result in a rapid permanent loss of vision.

Papillitis, papilledema, and neovascularization are seen under funduscopic examination leading to optic atrophy. Other less common manifestations include periphlebitis retinae, retinal hemorrhage, retinitis proliferans, band keratopathy, proptosis, and exophthalmos [155, 156].

Routine evaluation for eye involvement should include a slit-lamp examination and fundu‐ scopic examination to evaluate the anterior and posterior uveal tract, respectively [132]. Fluorescence angiography may also be considered if a posterior uveitis is suspected [156].

Oral corticosteroids are the mainstay of treatment of sarcoidosis. Systemic cytotoxic agents like methotrexate, azathioprine, and chlorambucil may be used in refractory cases. The visual prognosis of sarcoidosis is usually good [153].

Patients should be warned that skin atrophy could occur if steroids come into contact with skin surfaces. Intraocular corticosteroid injections can provide the patient with longer control of symptoms. Systemic steroids can be used if uveitis does not resolve with topical therapy or for cases where vision loss is possible. Alternative agents include tacrolimus, methotrexate, and photodynamic therapy [157].

Minocycline may be an option for patients with comorbidities that make steroids a less appealing option [158].

Interferon-alpha is commonly used to treat hepatitis C viral infection and has been reported to induce sarcoidosis and more recently ocular sarcoidosis with granulomatous panuveitis with choroidal granulomas.

In these cases topical steroids were used to treat ocular uveitis with systemic steroids for systemic findings.

### **Author details**

**10. Ocular manifestations in sarcoidosis**

132 Sarcoidosis

asymptomatically (with a "quiet eye").

anterior and posterior segments are involved.

prognosis of sarcoidosis is usually good [153].

permanent loss of vision.

[155, 156].

The eye or adnexa are affected in 25 to 80% of the sarcoidosis patients. The disease can involve

The disease can involve the orbit, lacrimal gland, anterior and posterior segments of the eye. Anterior uveitis is the most common manifestation, occurring in 65% of patients with ophthalmologic involvement [132]. Inflammation can affect the uveal tract leading to glaucoma, cataracts, and blindness. Typical sarcoid uveitis presents with bilateral muttonfat keratic precipitates, cells, flare, iris nodules, anterior and posterior synechia, and increased ocular pressure. Posterior involvement includes vitreitis, vasculitis, choroidal lesions, and optic neuropathy. Long-term complications are common, and cystoid macu‐ lar edema is the most important and sight-threatening consequence [153]. Acute uveitis presents with eye redness, cloudy vision, photophobia, and watering or can present

The gold standard for the diagnosis of sarcoidosis should be obtained with histologic exami‐ nation. However, an international workshop has recently established diagnostic criteria of "intraocular sarcoidosis" (sarcoidosis uveitis) on the basis of a combination of suggestive ophthalmological findings and laboratory tests, when biopsy is not performed or is negative. More recent techniques such as PET-scan and endoscopic ultrasound-guided fine-needle

Chronic anterior uveitis, with insidious symptoms leading to glaucoma and vision loss, is more common than acute anterior uveitis. In about 10 to 15% of patients with uveitis, both the

Lacrimal gland enlargement can cause dry eyes. Conjunctival follicles, dacryoscystitis, keratoconjunctivitis sicca, and retinal vasculitis also occur. Optic neuritis is an ophthalmo‐ logic emergency that requires immediate systemic therapy as it can result in a rapid

Papillitis, papilledema, and neovascularization are seen under funduscopic examination leading to optic atrophy. Other less common manifestations include periphlebitis retinae, retinal hemorrhage, retinitis proliferans, band keratopathy, proptosis, and exophthalmos

Routine evaluation for eye involvement should include a slit-lamp examination and fundu‐ scopic examination to evaluate the anterior and posterior uveal tract, respectively [132]. Fluorescence angiography may also be considered if a posterior uveitis is suspected [156].

Oral corticosteroids are the mainstay of treatment of sarcoidosis. Systemic cytotoxic agents like methotrexate, azathioprine, and chlorambucil may be used in refractory cases. The visual

Patients should be warned that skin atrophy could occur if steroids come into contact with skin surfaces. Intraocular corticosteroid injections can provide the patient with longer control

biopsy of intrathoracic nodes should be assessed in future prospective studies [154].

the orbit, lacrimal gland, anterior and posterior segments of the eye [153].

Luis Jara-Palomares, Candela Caballero-Eraso, Cesar Gutiérrez, Alvaro Donate and Jose Antonio Rodríguez-Portal

\*Address all correspondence to: luisoneumo@hotmail.com

Pneumologist, Medical-Surgical Unit of Respiratory Diseases. University Hospital Virgen del Rocio. Seville, Spain

### **References**


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**Chapter 6**

**Airways Disease in Sarcoidosis**

Additional information is available at the end of the chapter

Lupus pernio was first described by Kreibich and Kraus in 1908. [6] Pathognomic for sarcoidosis, Lupus pernio is a plaque-like lesion that is usually swollen, scaly or shiny. Typically, it occurs on the nose, cheeks, lips or ears. [7] Lupus pernio is most commonly observed in African-American women [8] and approximately 20% of all sarcoidosis patients with the lesion have co-morbid upper respiratory tract disease. [9] The skin lesion often involves the nasal mucosa and sometimes the underlying cartilage and nasal bones are

Nasal disease is usually associated with sinus disease. [10, 11] However, the clinical manifes‐ tations of nasal granulomas differ from sinus granulomas. Nasal mucus membrane granulo‐ mas may cause nasal obstruction, [11] epistaxis, crusting, rhinorrhea, post-nasal drip, pain and anosmia. [3] Obstruction is usually the most common presenting symptom when polypoid granulomatous lesions involve the nasal septum and the inferior turbinate. Fergie and colleagues retrospectively reviewed eight patients with nasal sarcoidosis and found that

On examination, the nasal mucosa is usually hypertrophic, erythematous and granular. It may also contain polyps, masses and/or asymmetric crust-like patches. The nasal bones may demonstrate a variety of radiographic abnormalities. [9, 10] Septal perforation is rare but granulomatous inflammation of the nasal cartilage (figure 2) may result in the classic "saddle nose" deformity. [13] Occasionally, granulomatous lesions may erode through the hard or soft

and reproduction in any medium, provided the original work is properly cited.

© 2013 Morgenthau; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

Adam S. Morgenthau

http://dx.doi.org/10.5772/55010

**1. Introduction**

destroyed. [7]

epiphora was present in 4 patients. [12]

palate, creating intraoral lesions or oral-nasal fistulae. [14]

**1.1. Nasal sarcoidosis**

### **Chapter 6**

## **Airways Disease in Sarcoidosis**

Adam S. Morgenthau

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55010

**1. Introduction**

#### **1.1. Nasal sarcoidosis**

Lupus pernio was first described by Kreibich and Kraus in 1908. [6] Pathognomic for sarcoidosis, Lupus pernio is a plaque-like lesion that is usually swollen, scaly or shiny. Typically, it occurs on the nose, cheeks, lips or ears. [7] Lupus pernio is most commonly observed in African-American women [8] and approximately 20% of all sarcoidosis patients with the lesion have co-morbid upper respiratory tract disease. [9] The skin lesion often involves the nasal mucosa and sometimes the underlying cartilage and nasal bones are destroyed. [7]

Nasal disease is usually associated with sinus disease. [10, 11] However, the clinical manifes‐ tations of nasal granulomas differ from sinus granulomas. Nasal mucus membrane granulo‐ mas may cause nasal obstruction, [11] epistaxis, crusting, rhinorrhea, post-nasal drip, pain and anosmia. [3] Obstruction is usually the most common presenting symptom when polypoid granulomatous lesions involve the nasal septum and the inferior turbinate. Fergie and colleagues retrospectively reviewed eight patients with nasal sarcoidosis and found that epiphora was present in 4 patients. [12]

On examination, the nasal mucosa is usually hypertrophic, erythematous and granular. It may also contain polyps, masses and/or asymmetric crust-like patches. The nasal bones may demonstrate a variety of radiographic abnormalities. [9, 10] Septal perforation is rare but granulomatous inflammation of the nasal cartilage (figure 2) may result in the classic "saddle nose" deformity. [13] Occasionally, granulomatous lesions may erode through the hard or soft palate, creating intraoral lesions or oral-nasal fistulae. [14]

© 2013 Morgenthau; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

nation often demonstrates erythematous, friable, hypertrophied mucosa. Crusting, studding, plaque-like changes or polyps may also be visualized. Rarely, granulomatous lesions extend out of the sinuses and into the orbit, resulting in proptosis and/or decreased unilateral visual acuity. [16] Sarcoidosis of the sinuses is generally a chronic and recalcitrant form of the disease

Airways Disease in Sarcoidosis http://dx.doi.org/10.5772/55010 147

The epiglottis, aryepiglottic folds, arytenoids, false cords and subglottis are the most com‐ monly affected regions in the larynx. The true vocal cords are relatively devoid of lymphatic tissue and are rarely ridden with disease. [19] Granulomatous involvement of the larynx may cause life-threatening stridor or dysphagia. [10] On examination, the involved laryngeal mucosa is typically pale pink, granular and edenomatous. Lesions vary in their size and shape. Localized submucosal induration, punctate nodules or polypoid masses may be present. In one review of 40 patients with laryngeal sarcoidosis, the presenting symptoms were: dyspha‐ gia (85%), hoarseness (63%), dyspnea or stridor (47%) and cough (13%). [20] Ulceration of the mucosa is rare. Patients also present with hoarseness, dysphonia, cough, dyspnea, a sensation

Hoarseness is typically caused by granulomatous laryngitis. However, laryngeal sarcoidosis may cause hoarseness by two additional mechanisms. [22, 23] The first involves granuloma‐ tous infiltration of the vagus nerve, resulting in a polyneuropathy. Limited data suggests that vagal polyneuropathy is rare [24] and if present, is typically associated with other cranial neuropathies. [21] In rare cases, hoarseness may result from mediastinal lymphadenopathy that compresses the recurrent laryngeal nerve, resulting in vocal cord paralysis. The left recurrent laryngeal nerve is affected in more than 95% of cases. [21, 25] The predilection for left-sided injury results from the longer and more vulnerable course of the left recurrent

In one report, a young female presented with daytime hypersomnolence and snoring. [26]

Nasopharyngoscopy demonstrated an irregularly shaped and narrowed subglottis. Subse‐ quent biopsy confirmed the presence of non-caseating granulomas. The patient was diagnosed with obstructive sleep apnea, secondary to laryngeal sarcoidosis. To determine the prevalence and risk factors for obstructive sleep apnea in sarcoidosis patients, 83 patients with sarcoidosis were prospectively evaluated. [27] The Epworth Sleepiness Scale was used to assess enrolled patients. A control group of 91 patients were similarly screened. Patients with a positive sleep questionnaire were referred for sleep studies. A total of 14 sarcoidosis patients (17%) were found to have sleep apnea, which was significantly higher than in the control group where 3/91 were found to have obstructive disease (3%, p < 0.001). [27] Lupus pernio was significantly more frequent in the sleep apnea group. [27] Although granulomatous laryngitis may be associated with obstructive sleep apnea, obstructive sleep apnea in patients with sarcoidosis usually results from obesity secondary to the administration of chronic corticosteroids.

that requires prolonged systemic therapy. [6, 17, 18]

of a lump in the throat and obstructive sleep apnea. [21]

laryngeal nerve through the mediastinum.

**3. Laryngeal sarcoidosis**

**Figure 1.** Sarcoidosis patient with Lupus Pernio.

**Figure 2.** Bronchcoscopic appearance of endobronchial sarcoidosis demonstrating nodules and inflamed mucosa that narrows the right upper lobe bronchus.

#### **2. Sinus sarcoidosis**

The symptoms of nasal obstruction and chronic sinusitis often occur in patients concomitantly. [10, 11] The most common symptoms associated with sarcoidosis of the sinuses are recurrent infections, epistaxis, periorbital tenderness, post-nasal drip and headache. [15] Patients with sarcoidosis of the sinuses usually have involvement of multiple organ systems. [11] Sarcoidal lesions in the sinus mucosa are generally similar to those found in the nasal mucosa. Exami‐ nation often demonstrates erythematous, friable, hypertrophied mucosa. Crusting, studding, plaque-like changes or polyps may also be visualized. Rarely, granulomatous lesions extend out of the sinuses and into the orbit, resulting in proptosis and/or decreased unilateral visual acuity. [16] Sarcoidosis of the sinuses is generally a chronic and recalcitrant form of the disease that requires prolonged systemic therapy. [6, 17, 18]

### **3. Laryngeal sarcoidosis**

**Figure 1.** Sarcoidosis patient with Lupus Pernio.

146 Sarcoidosis

narrows the right upper lobe bronchus.

**2. Sinus sarcoidosis**

**Figure 2.** Bronchcoscopic appearance of endobronchial sarcoidosis demonstrating nodules and inflamed mucosa that

The symptoms of nasal obstruction and chronic sinusitis often occur in patients concomitantly. [10, 11] The most common symptoms associated with sarcoidosis of the sinuses are recurrent infections, epistaxis, periorbital tenderness, post-nasal drip and headache. [15] Patients with sarcoidosis of the sinuses usually have involvement of multiple organ systems. [11] Sarcoidal lesions in the sinus mucosa are generally similar to those found in the nasal mucosa. Exami‐

The epiglottis, aryepiglottic folds, arytenoids, false cords and subglottis are the most com‐ monly affected regions in the larynx. The true vocal cords are relatively devoid of lymphatic tissue and are rarely ridden with disease. [19] Granulomatous involvement of the larynx may cause life-threatening stridor or dysphagia. [10] On examination, the involved laryngeal mucosa is typically pale pink, granular and edenomatous. Lesions vary in their size and shape. Localized submucosal induration, punctate nodules or polypoid masses may be present. In one review of 40 patients with laryngeal sarcoidosis, the presenting symptoms were: dyspha‐ gia (85%), hoarseness (63%), dyspnea or stridor (47%) and cough (13%). [20] Ulceration of the mucosa is rare. Patients also present with hoarseness, dysphonia, cough, dyspnea, a sensation of a lump in the throat and obstructive sleep apnea. [21]

Hoarseness is typically caused by granulomatous laryngitis. However, laryngeal sarcoidosis may cause hoarseness by two additional mechanisms. [22, 23] The first involves granuloma‐ tous infiltration of the vagus nerve, resulting in a polyneuropathy. Limited data suggests that vagal polyneuropathy is rare [24] and if present, is typically associated with other cranial neuropathies. [21] In rare cases, hoarseness may result from mediastinal lymphadenopathy that compresses the recurrent laryngeal nerve, resulting in vocal cord paralysis. The left recurrent laryngeal nerve is affected in more than 95% of cases. [21, 25] The predilection for left-sided injury results from the longer and more vulnerable course of the left recurrent laryngeal nerve through the mediastinum.

In one report, a young female presented with daytime hypersomnolence and snoring. [26]

Nasopharyngoscopy demonstrated an irregularly shaped and narrowed subglottis. Subse‐ quent biopsy confirmed the presence of non-caseating granulomas. The patient was diagnosed with obstructive sleep apnea, secondary to laryngeal sarcoidosis. To determine the prevalence and risk factors for obstructive sleep apnea in sarcoidosis patients, 83 patients with sarcoidosis were prospectively evaluated. [27] The Epworth Sleepiness Scale was used to assess enrolled patients. A control group of 91 patients were similarly screened. Patients with a positive sleep questionnaire were referred for sleep studies. A total of 14 sarcoidosis patients (17%) were found to have sleep apnea, which was significantly higher than in the control group where 3/91 were found to have obstructive disease (3%, p < 0.001). [27] Lupus pernio was significantly more frequent in the sleep apnea group. [27] Although granulomatous laryngitis may be associated with obstructive sleep apnea, obstructive sleep apnea in patients with sarcoidosis usually results from obesity secondary to the administration of chronic corticosteroids.

### **4. Tracheal sarcoidosis**

Sarcoidal involvement of the trachea is rare [28] and the literature on tracheal sarcodosis is sparse. Tracheal stenosis and dystonia are the primary manifestations that have been described. [28, 29] Brandstetter and associates [30] described a patient who complained of deteriorating voice strength for 30 years and eventually, stridulent breathing that was refractory to corticosteriods. In 1949, Lemoine described tracheal dystonia (tracheal collapse most pronounced on expira‐ tion) in sarcoidosis. Ellefsen detailed a 44-year-old female who complained of progressive dyspnea for 4 years prior to admission to the hospital. [29] She eventually developed wheezing and a severe nonproductive cough. Physical exam showed stridor and wheezing.

and newer imaging modalities such as hyperpolarized 3-H MRI, [41, 42] in patients with pulmo‐ nary sarcoidosis who have obstructive airways disease. Peripheral airway obstruction with involvement of small airways may be caused by the formation of granulomas in a perilymphat‐ ic distribution along the bronchovascular bundles. [41, 43] Small airways dysfunction can be measured by forced expiratory flow during the middle half of the forced expiratory curve (MMEF25-75%), forced expiratory volume at 3 seconds (FEV3) ratio of the residual volume to the total lung capacity (RV/TLC). In one study, the extent of air trapping on HRCT correlated significant‐ ly with RV/TLC and MMEF25-75%. [41, 43] In other studies, however, these physiologic measure‐

Airways Disease in Sarcoidosis http://dx.doi.org/10.5772/55010 149

Patients with small airways disease typically present with progressive dyspnea, cough and wheeze. They may also exhibit stridulent breathing. Lung auscultation demonstrates wheez‐

> **INFECTIOUS NON-INFECTIOUS** Tuberculosis Sarcoidosis Atypical Mycobacterial Disease Wegener's Granulomatosis Syphilis Berylliosis Leprosy Silicosis Aspergillosis Hypersensitivity Pneumonitis

Histoplasmosis Lymphoma Rhinoscleroma Cocaine Coccidioidomycosis Churg-Strauss Syndrome Toxoplasmosis Talc

"Reprinted from Mukhopadhyay, S. et al…, Granulomatous Lung Disease: An Approach to the Differential Diagnosis. May 2010, Vol. 134, No. 5, pp. 667-690 with permission from *Archives of Pathology & Laboratory Medicine*. Copyright

Actinomycosis Lymphoid Interstitial Pneumonia Cryptoccosis Rheumatoid Nodule

ments were highly variable and provided limited clinical information. [43-45]

ing, stridor or squeaks.

Nares Nasal Septum Sinuses Larynx Vocal Cords Trachea Bronchi Bronchioles

Skin of the Nose (Lupus Pernio)

**Table 1.** Airway Involvement in Sarcoidosis

2010. College of American Pathologists."

**Table 2.** Differential Diagnosis of Granulomatous Airways Diseases

### **5. Bronchial sarcoidosis**

Bronchial sarcoidosis was first described at autopsy by Bernstein and colleagues in 1929 and subsequently on bronchcoscopy by Benedict and Castleman in 1941. [31] Numerous case series have followed. [32-37] Granulomatous lesions typically occur in the bronchial submucosa. [37] The bronchial mucosa often appears inflamed with small or large nodules containing granu‐ lomas. [37] (Figure 2) Granulomatous involvement of the bronchi may cause edema and/or an endobronchial masses that results in reversible narrowing of the large airways. [33, 36, 37] Irreversible narrowing, especially of the right middle lobe bronchus, results from cicatricial stenosis. [33] Reversible or irreversible bronchial stenosis occurs more commonly in the presence of end-stage pulmonary fibrosis. But bronchostenosis may occur in milder stages of the disease. [33, 36, 37] Bronchial sarcoidosis may be isolated (one stenotic point) or diffuse (multiple stenotic points) involving the lobar or segmental bronchi. Compressive mediastinal and/or bronchopulmonary lymphadenopathy is rarely a cause of stenoses at these locations within the airway. [38, 39]

Patients with bronchial sarcoidosis present with dyspnea, cough and wheezing that is often misdiagnosed as asthma. [10] The symptoms generally progress and are refractory to bron‐ chodilators and inhaled corticosteroids. Bronchial sarcoidosis is suggested by obstructive airways disease (a reduced ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC]) that may be accompanied by airways hyperreactivity on pulmonary function tests. Bronchoscopic inspection of the airways with or without biopsy of the parenchyma is the most efficient method to confirm the diagnosis. Endobronchial involvement is common in sarcoidosis. Endobronchial biopsy has a yield comparable to transbronchial biopsy and can safely increase the diagnostic value of fiberoptic bronchoscopy. Performance of endobronchial biopsies should routinely be considered in cases of suspected sarcoidosis.

### **6. Small airways sarcoidosis**

Small airways disease is an underappreciated manifestation of pulmonary sarcoidosis. Region‐ al air trapping, indicative of small airways disease, may be visualized on expiratory HRCT [40] and newer imaging modalities such as hyperpolarized 3-H MRI, [41, 42] in patients with pulmo‐ nary sarcoidosis who have obstructive airways disease. Peripheral airway obstruction with involvement of small airways may be caused by the formation of granulomas in a perilymphat‐ ic distribution along the bronchovascular bundles. [41, 43] Small airways dysfunction can be measured by forced expiratory flow during the middle half of the forced expiratory curve (MMEF25-75%), forced expiratory volume at 3 seconds (FEV3) ratio of the residual volume to the total lung capacity (RV/TLC). In one study, the extent of air trapping on HRCT correlated significant‐ ly with RV/TLC and MMEF25-75%. [41, 43] In other studies, however, these physiologic measure‐ ments were highly variable and provided limited clinical information. [43-45]

Patients with small airways disease typically present with progressive dyspnea, cough and wheeze. They may also exhibit stridulent breathing. Lung auscultation demonstrates wheez‐ ing, stridor or squeaks.


**Table 1.** Airway Involvement in Sarcoidosis

**4. Tracheal sarcoidosis**

148 Sarcoidosis

**5. Bronchial sarcoidosis**

within the airway. [38, 39]

**6. Small airways sarcoidosis**

Sarcoidal involvement of the trachea is rare [28] and the literature on tracheal sarcodosis is sparse. Tracheal stenosis and dystonia are the primary manifestations that have been described. [28, 29] Brandstetter and associates [30] described a patient who complained of deteriorating voice strength for 30 years and eventually, stridulent breathing that was refractory to corticosteriods. In 1949, Lemoine described tracheal dystonia (tracheal collapse most pronounced on expira‐ tion) in sarcoidosis. Ellefsen detailed a 44-year-old female who complained of progressive dyspnea for 4 years prior to admission to the hospital. [29] She eventually developed wheezing

Bronchial sarcoidosis was first described at autopsy by Bernstein and colleagues in 1929 and subsequently on bronchcoscopy by Benedict and Castleman in 1941. [31] Numerous case series have followed. [32-37] Granulomatous lesions typically occur in the bronchial submucosa. [37] The bronchial mucosa often appears inflamed with small or large nodules containing granu‐ lomas. [37] (Figure 2) Granulomatous involvement of the bronchi may cause edema and/or an endobronchial masses that results in reversible narrowing of the large airways. [33, 36, 37] Irreversible narrowing, especially of the right middle lobe bronchus, results from cicatricial stenosis. [33] Reversible or irreversible bronchial stenosis occurs more commonly in the presence of end-stage pulmonary fibrosis. But bronchostenosis may occur in milder stages of the disease. [33, 36, 37] Bronchial sarcoidosis may be isolated (one stenotic point) or diffuse (multiple stenotic points) involving the lobar or segmental bronchi. Compressive mediastinal and/or bronchopulmonary lymphadenopathy is rarely a cause of stenoses at these locations

Patients with bronchial sarcoidosis present with dyspnea, cough and wheezing that is often misdiagnosed as asthma. [10] The symptoms generally progress and are refractory to bron‐ chodilators and inhaled corticosteroids. Bronchial sarcoidosis is suggested by obstructive airways disease (a reduced ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC]) that may be accompanied by airways hyperreactivity on pulmonary function tests. Bronchoscopic inspection of the airways with or without biopsy of the parenchyma is the most efficient method to confirm the diagnosis. Endobronchial involvement is common in sarcoidosis. Endobronchial biopsy has a yield comparable to transbronchial biopsy and can safely increase the diagnostic value of fiberoptic bronchoscopy. Performance of endobronchial

Small airways disease is an underappreciated manifestation of pulmonary sarcoidosis. Region‐ al air trapping, indicative of small airways disease, may be visualized on expiratory HRCT [40]

biopsies should routinely be considered in cases of suspected sarcoidosis.

and a severe nonproductive cough. Physical exam showed stridor and wheezing.


"Reprinted from Mukhopadhyay, S. et al…, Granulomatous Lung Disease: An Approach to the Differential Diagnosis. May 2010, Vol. 134, No. 5, pp. 667-690 with permission from *Archives of Pathology & Laboratory Medicine*. Copyright 2010. College of American Pathologists."

**Table 2.** Differential Diagnosis of Granulomatous Airways Diseases

#### **6.1. Airway Hyperreactivity (AHR)**

The incidence of airway hyperreactivity (AHR) in sarcoidosis is highly variable. Airway hyperreactivity has been observed in approximately 20%--50% of sarcoidosis patients. [46, 47] The statistical discrepancy probably results from different patient populations, study designs and different definitions of sarcoidosis and AHR.

upper lobe may result in the radiographic S-sign of Golden, which is commonly associated with cancer. Resolution of atelectasis is variable and it may occur even after several years. [54]

Airways Disease in Sarcoidosis http://dx.doi.org/10.5772/55010 151

Chronic, progressive, end-stage, pulmonary fibrosis with traction bronchiectasis, often referred to as "honeycomb lung", develops in approximately 25% of patients with chronic pulmonary sarcoidosis. [40, 55] The condition is characterized by parenchymal fibrosis, bronchiolectasis and enlarged, dilated air spaces. It usually occurs subpleurally within the upper regions of the lung [40, 56] (figure 3). Oxygenation and ventilatory function are impaired. Pulmonary function tests demonstrate severe restriction and gas transfer abnor‐ malities. Importantly, fibrosis characterized by a stage IV radiographic pattern, rarely re‐

**Figure 3.** Sarcoidosis patient with granulomatous inflammation of the nasal cartilage

Bullea (thin-walled air spaces in the lungs) may develop in patients with advanced pulmonary sarcoidosis. Most sarcoidosis patients with bullous disease do not exhibit an extensive smoking history and have airflow obstruction on pulmonary function tests. [10, 57] Dilatation and rupture of bullae probably results from granulomatous bronchostenosis. [58] Bullae may develop secondary to destruction of alveolar walls by alveolitis. [58] Bullous rupture may cause

Giant bullous changes in sarcoidosis may rarely cause the Vanishing Lung Syndrome. [59] First described by Burke in 1937, the Vanishing Lung Syndrome describes an end stage of

**6.3. Fibrosis**

sponds to treatment.

**6.4. Bullous disease**

pneumothorax.

Airway hyperreactivity has important clinical and prognostic implications in sarcoidosis. [47] Many patients with sarcoidosis exhibit normal pulmonary function and imaging but complain of cough, dyspnea and wheeze. The wall of the airway may be narrowed and thickened as a result of airway hyperreactivity or may collapse from an extrinsic pathologic process in the lung. Airway hyperreactivity in sarcoidosis may also cause chronic airflow obstruction, which has been associated with a poor prognosis. [47, 48] Fixed airway obstruction has been shown to nearly double the risk of mortality. [47]

The prevalence of AHR, as demonstrated by a positive methacholine challenge test, is significantly higher in sarcoidosis patients compared to normal controls. [1, 47] It is unclear whether AHR is a physiologic manifestation of endobronchial sarcoidosis or reversible airways disease in asthma. Rarely, asthma may be associated with sarcoidosis. [49] Airway hyperreactivity in sarcoidosis and reversible airways disease in asthma may often be distin‐ guished by response to inhaled corticosteroids and/or beta-agonists. Asthmatic reactive airways disease usually improves with these medications. But AHR in sarcoidosis commonly requires treatment with oral corticosteroids. [33, 47] In many cases, AHR in sarcoidosis does not improve with systemic corticosteroids.

Importantly, cough and wheeze secondary to AHR (as demonstrated by positive methacholine challenge testing) should not be confused with cough and wheeze unrelated to AHR. *Sarcoidal cough and wheeze unrelated to AHR* responds favorably to inhaled corticosteroids and/or betaagonists as does *asthmatic cough and wheeze related to AHR*. [47] Sarcoidal cough and wheeze associated with AHR, however, may require treatment with oral corticosteroids, which is often ineffective.

Several studies suggests that AHR in sarcoidosis correlates with both the degree of alveolitis and angiotensin converting enzyme (ACE) levels in bronchoalveolar lavage (BAL) fluid and serum. [50] In addition, higher serum ACE levels were found in sarcodosis patients with hyperreactivi‐ ty. [47] Finally, patients with AHR were more likely to have a positive endobronchial biopsy (9/9, 100%) compared to individuals without hyperreactivity (15/33, 45.5%), which suggests that AHR is present in patients with more pronounced bronchial inflammation. [47]

#### **6.2. Atelectasis**

Lobar atelectasis may result from occlusion of a lobar bronchus. Bronchial obstruction may be caused by one of two mechanisms: endobronchial stenosis [37] or rarely, by extrinsic compres‐ sion of the bronchus by enlarged lymph nodes. [51, 52] Atelectasis of the middle lobe is most common but atelectasis of the right upper lobe has also been reported. [53] The middle lobe is particularly susceptible to collapse because it has a small bronchial lumen, surrounded by many lymph nodes and emerges at a right angle from the bronchus intermedius. Collapse of the right upper lobe may result in the radiographic S-sign of Golden, which is commonly associated with cancer. Resolution of atelectasis is variable and it may occur even after several years. [54]

#### **6.3. Fibrosis**

**6.1. Airway Hyperreactivity (AHR)**

150 Sarcoidosis

to nearly double the risk of mortality. [47]

not improve with systemic corticosteroids.

ineffective.

**6.2. Atelectasis**

designs and different definitions of sarcoidosis and AHR.

The incidence of airway hyperreactivity (AHR) in sarcoidosis is highly variable. Airway hyperreactivity has been observed in approximately 20%--50% of sarcoidosis patients. [46, 47] The statistical discrepancy probably results from different patient populations, study

Airway hyperreactivity has important clinical and prognostic implications in sarcoidosis. [47] Many patients with sarcoidosis exhibit normal pulmonary function and imaging but complain of cough, dyspnea and wheeze. The wall of the airway may be narrowed and thickened as a result of airway hyperreactivity or may collapse from an extrinsic pathologic process in the lung. Airway hyperreactivity in sarcoidosis may also cause chronic airflow obstruction, which has been associated with a poor prognosis. [47, 48] Fixed airway obstruction has been shown

The prevalence of AHR, as demonstrated by a positive methacholine challenge test, is significantly higher in sarcoidosis patients compared to normal controls. [1, 47] It is unclear whether AHR is a physiologic manifestation of endobronchial sarcoidosis or reversible airways disease in asthma. Rarely, asthma may be associated with sarcoidosis. [49] Airway hyperreactivity in sarcoidosis and reversible airways disease in asthma may often be distin‐ guished by response to inhaled corticosteroids and/or beta-agonists. Asthmatic reactive airways disease usually improves with these medications. But AHR in sarcoidosis commonly requires treatment with oral corticosteroids. [33, 47] In many cases, AHR in sarcoidosis does

Importantly, cough and wheeze secondary to AHR (as demonstrated by positive methacholine challenge testing) should not be confused with cough and wheeze unrelated to AHR. *Sarcoidal cough and wheeze unrelated to AHR* responds favorably to inhaled corticosteroids and/or betaagonists as does *asthmatic cough and wheeze related to AHR*. [47] Sarcoidal cough and wheeze associated with AHR, however, may require treatment with oral corticosteroids, which is often

Several studies suggests that AHR in sarcoidosis correlates with both the degree of alveolitis and angiotensin converting enzyme (ACE) levels in bronchoalveolar lavage (BAL) fluid and serum. [50] In addition, higher serum ACE levels were found in sarcodosis patients with hyperreactivi‐ ty. [47] Finally, patients with AHR were more likely to have a positive endobronchial biopsy (9/9, 100%) compared to individuals without hyperreactivity (15/33, 45.5%), which suggests that AHR

Lobar atelectasis may result from occlusion of a lobar bronchus. Bronchial obstruction may be caused by one of two mechanisms: endobronchial stenosis [37] or rarely, by extrinsic compres‐ sion of the bronchus by enlarged lymph nodes. [51, 52] Atelectasis of the middle lobe is most common but atelectasis of the right upper lobe has also been reported. [53] The middle lobe is particularly susceptible to collapse because it has a small bronchial lumen, surrounded by many lymph nodes and emerges at a right angle from the bronchus intermedius. Collapse of the right

is present in patients with more pronounced bronchial inflammation. [47]

Chronic, progressive, end-stage, pulmonary fibrosis with traction bronchiectasis, often referred to as "honeycomb lung", develops in approximately 25% of patients with chronic pulmonary sarcoidosis. [40, 55] The condition is characterized by parenchymal fibrosis, bronchiolectasis and enlarged, dilated air spaces. It usually occurs subpleurally within the upper regions of the lung [40, 56] (figure 3). Oxygenation and ventilatory function are impaired. Pulmonary function tests demonstrate severe restriction and gas transfer abnor‐ malities. Importantly, fibrosis characterized by a stage IV radiographic pattern, rarely re‐ sponds to treatment.

**Figure 3.** Sarcoidosis patient with granulomatous inflammation of the nasal cartilage

#### **6.4. Bullous disease**

Bullea (thin-walled air spaces in the lungs) may develop in patients with advanced pulmonary sarcoidosis. Most sarcoidosis patients with bullous disease do not exhibit an extensive smoking history and have airflow obstruction on pulmonary function tests. [10, 57] Dilatation and rupture of bullae probably results from granulomatous bronchostenosis. [58] Bullae may develop secondary to destruction of alveolar walls by alveolitis. [58] Bullous rupture may cause pneumothorax.

Giant bullous changes in sarcoidosis may rarely cause the Vanishing Lung Syndrome. [59] First described by Burke in 1937, the Vanishing Lung Syndrome describes an end stage of diffuse panacinar emphysema in which large air spaces develop, further impairing lung function. [59] Miller and associates reported two cases of the Vanishing Lung Syndrome. Postmortem analysis of the lungs demonstrated that the bullae were quite different from the localized air spaces frequently seen in chronic pulmonary sarcoidosis. [10, 60]

and empyema. The authors concluded that surgical resection should generally be avoided in patients with bilateral disease and compromised pulmonary function. The indication for surgery in all patients, especially those with poor pulmonary function, should be recurrent hemoptysis because it may cause exsanguinating hemorrhage, which poses a greater risk to

Airways Disease in Sarcoidosis http://dx.doi.org/10.5772/55010 153

Computed tomography (CT) is often the imaging method of choice for sarcoidosis of the upper and lower respiratory tract. [40] Braun and associates analyzed the CT findings of 15 patients with sinonasal sarcoidosis. [20] A spectrum of abnormalities were evaluated: nodular lesions of the septum and/or inferior turbinates; mucosal thickening and complete or subtotal opacification of the ethmoidal, maxillary and/or sphenoid sinuses; obstruction of the ostio‐ meatal units and of the upper part of the nasal cavities; turbinoseptal synechiae; destruction or erosion of the turbinates, nasal bones, septum, ethmoid air cells and sphenoid sinus.

CT scan has a high sensitivity for detecting sarcoidosis of the larynx or trachea. [65] Typically,

Airways sarcoidosis produces a variety of abnormalities on CT scan of the lungs. Several CT studies performed at near residual volume (end expiration) have demonstrated air-trapping in pulmonary sarcoidosis. [40, 66, 67] Davies and colleagues reported that air-trapping on expiratory CT was present in 95% of 21 sarcoidosis patients and correlated with physiologic obstruction by percentage predicted residual volume (RV)/ total lung capacity (TLC) (p < 0.05) and percentage predicted maximal mid-expiratory flow rate between 25% and 75% of the vital capacity (VC) (p < 0.05). [41] The CT may also demonstrate focal bronchial lesions, atelectasis, bullous disease, fibrosis/honeycombing, cavitary lung disease, bronchiectasis (saccular or

The respiratory tract is typically divided into the upper and lower airways at the level of the vocal cords. The physiology of obstruction to the upper airways depends on the location of the obstruction (intrathoracic or extrathoracic) and whether it is fixed or variable within the respiratory cycle. Granulomatous involvement of the larynx results in a fixed upper airway obstruction. When tracheal sarcoidosis results in stenosis, it may cause a fixed upper airway obstruction (figure 4) or a variable extrathoracic or intrathoracic obstruction (figure 4) depending on whether it is located above (extrathoracic) or below (intrathoracic) the thoracic inlet (level of the supra-sternal notch). In a fixed upper airway obstruction, there is flattening of the inspiratory and expiratory limbs of the flow volume loop. A variable extrathoracic obstruction causes flattening of the inspiratory portion of the flow volume loop, while a variable intrathoracic obstruction causes flattening of the expiratory portion of the loop.

the patient than surgical intervention. [64]

the CT demonstrates stenosis of the larynx and trachea.

**7. Imaging**

cylindrical) and mycetomas

**8. Physiology**

#### **6.5. Cavitary lung disease, bronchiectasis and mycetomas**

Although the terms cyst and cavity have overlapping meanings and may be used interchange‐ ably, the technical definitions of these terms are different. Cysts are clearly defined aircontaining space surrounded by a relatively thin (≤ 4 mm) wall. A cavity, in contrast, is meant to describe an air-containing lesion with a relatively thick (> 4 mm) wall or within an area of a surrounding infiltrate or mass. The distinction is useful because there is a different diagnostic approach to these anatomic structures. [61]

True cavitary lung disease, which results from necrosis of granulomatous areas creating airspaces within thick walls or within a fibrotic mass, is rare in sarcoidosis. Sarcoidal cavities must be differentiated from those associated with mycobacterial infection. The radiographic cystic changes that occur in advanced sarcoidosis are typically consistent with saccular bronchiectasis, rather than true cavitations. [57, 61] Saccular or cylindrical bronchiectasis likely results from bronchial wall injury by granulomas, superimposed bronchial infection and radial traction by peribronchial scar tissue. Colonization of the bronchiectatic sacs by Aspergillus sp., may result in the development of an aspergilloma. Patients with aspergillomas complicating sarcoidosis may have life-threatening hemoptysis but, as a result of their advanced lung disease, are usually high-risk surgical candidates. [62]

Intracavitary instillation of antifungal agents is an alternative treatment in patients with severe pulmonary dysfunction who are poor operative risks. Percutaneous instillation of amphoter‐ icin B guided by CT scans may be effective for the treatment of aspergilloma. [63] In several cases, the intervention has led to resolution of hemoptysis. [63] The response to percutaneous injection of amphotericin B appears to be sustainable for several months. [63]

Israel and associates evaluated the role of surgery in 38 sarcoidosis patients with pulmonary aspergillomas, 10 of whom were considered satisfactory operative candidates. [64] Satisfactory candidates demonstrated a forced vital capacity greater than 50% predicted and a resting PaO2 greater than 80 mmHg. The indication for surgical resection in satisfactory and unsatisfactory candidates was recurrent hemoptysis. Seven satisfactory and 7 unsatisfactory candidates underwent segmental resection, lobectomy or bilobectomy. The authors did not specify the type of procedure that each patient received. Patients were followed postoperatively for an unspecified duration. Among the 7 satisfactory candidates who underwent resection, 1 patient died from empyema immediately after surgery. Three of 7 patients with unsatisfactory pulmonary function died of respiratory failure 1 month, 11 months and 27 months, respec‐ tively, after surgery. Twenty-one patients with poor pulmonary function did not have surgery. Four patients died of recurrent hemorrhage 4 months to 3 years after discovery of the asper‐ gilloma. Eleven patients died of respiratory failure and 6 survived at the time of publication (1982) although it is unclear when these patients were diagnosed with their aspergilloma. The principle complications of surgical resection were prolonged air leaks, bronchopleural fistulae and empyema. The authors concluded that surgical resection should generally be avoided in patients with bilateral disease and compromised pulmonary function. The indication for surgery in all patients, especially those with poor pulmonary function, should be recurrent hemoptysis because it may cause exsanguinating hemorrhage, which poses a greater risk to the patient than surgical intervention. [64]

### **7. Imaging**

diffuse panacinar emphysema in which large air spaces develop, further impairing lung function. [59] Miller and associates reported two cases of the Vanishing Lung Syndrome. Postmortem analysis of the lungs demonstrated that the bullae were quite different from the

Although the terms cyst and cavity have overlapping meanings and may be used interchange‐ ably, the technical definitions of these terms are different. Cysts are clearly defined aircontaining space surrounded by a relatively thin (≤ 4 mm) wall. A cavity, in contrast, is meant to describe an air-containing lesion with a relatively thick (> 4 mm) wall or within an area of a surrounding infiltrate or mass. The distinction is useful because there is a different diagnostic

True cavitary lung disease, which results from necrosis of granulomatous areas creating airspaces within thick walls or within a fibrotic mass, is rare in sarcoidosis. Sarcoidal cavities must be differentiated from those associated with mycobacterial infection. The radiographic cystic changes that occur in advanced sarcoidosis are typically consistent with saccular bronchiectasis, rather than true cavitations. [57, 61] Saccular or cylindrical bronchiectasis likely results from bronchial wall injury by granulomas, superimposed bronchial infection and radial traction by peribronchial scar tissue. Colonization of the bronchiectatic sacs by Aspergillus sp., may result in the development of an aspergilloma. Patients with aspergillomas complicating sarcoidosis may have life-threatening hemoptysis but, as a result of their advanced lung

Intracavitary instillation of antifungal agents is an alternative treatment in patients with severe pulmonary dysfunction who are poor operative risks. Percutaneous instillation of amphoter‐ icin B guided by CT scans may be effective for the treatment of aspergilloma. [63] In several cases, the intervention has led to resolution of hemoptysis. [63] The response to percutaneous

Israel and associates evaluated the role of surgery in 38 sarcoidosis patients with pulmonary aspergillomas, 10 of whom were considered satisfactory operative candidates. [64] Satisfactory candidates demonstrated a forced vital capacity greater than 50% predicted and a resting PaO2 greater than 80 mmHg. The indication for surgical resection in satisfactory and unsatisfactory candidates was recurrent hemoptysis. Seven satisfactory and 7 unsatisfactory candidates underwent segmental resection, lobectomy or bilobectomy. The authors did not specify the type of procedure that each patient received. Patients were followed postoperatively for an unspecified duration. Among the 7 satisfactory candidates who underwent resection, 1 patient died from empyema immediately after surgery. Three of 7 patients with unsatisfactory pulmonary function died of respiratory failure 1 month, 11 months and 27 months, respec‐ tively, after surgery. Twenty-one patients with poor pulmonary function did not have surgery. Four patients died of recurrent hemorrhage 4 months to 3 years after discovery of the asper‐ gilloma. Eleven patients died of respiratory failure and 6 survived at the time of publication (1982) although it is unclear when these patients were diagnosed with their aspergilloma. The principle complications of surgical resection were prolonged air leaks, bronchopleural fistulae

injection of amphotericin B appears to be sustainable for several months. [63]

localized air spaces frequently seen in chronic pulmonary sarcoidosis. [10, 60]

**6.5. Cavitary lung disease, bronchiectasis and mycetomas**

approach to these anatomic structures. [61]

152 Sarcoidosis

disease, are usually high-risk surgical candidates. [62]

Computed tomography (CT) is often the imaging method of choice for sarcoidosis of the upper and lower respiratory tract. [40] Braun and associates analyzed the CT findings of 15 patients with sinonasal sarcoidosis. [20] A spectrum of abnormalities were evaluated: nodular lesions of the septum and/or inferior turbinates; mucosal thickening and complete or subtotal opacification of the ethmoidal, maxillary and/or sphenoid sinuses; obstruction of the ostio‐ meatal units and of the upper part of the nasal cavities; turbinoseptal synechiae; destruction or erosion of the turbinates, nasal bones, septum, ethmoid air cells and sphenoid sinus.

CT scan has a high sensitivity for detecting sarcoidosis of the larynx or trachea. [65] Typically, the CT demonstrates stenosis of the larynx and trachea.

Airways sarcoidosis produces a variety of abnormalities on CT scan of the lungs. Several CT studies performed at near residual volume (end expiration) have demonstrated air-trapping in pulmonary sarcoidosis. [40, 66, 67] Davies and colleagues reported that air-trapping on expiratory CT was present in 95% of 21 sarcoidosis patients and correlated with physiologic obstruction by percentage predicted residual volume (RV)/ total lung capacity (TLC) (p < 0.05) and percentage predicted maximal mid-expiratory flow rate between 25% and 75% of the vital capacity (VC) (p < 0.05). [41] The CT may also demonstrate focal bronchial lesions, atelectasis, bullous disease, fibrosis/honeycombing, cavitary lung disease, bronchiectasis (saccular or cylindrical) and mycetomas

### **8. Physiology**

The respiratory tract is typically divided into the upper and lower airways at the level of the vocal cords. The physiology of obstruction to the upper airways depends on the location of the obstruction (intrathoracic or extrathoracic) and whether it is fixed or variable within the respiratory cycle. Granulomatous involvement of the larynx results in a fixed upper airway obstruction. When tracheal sarcoidosis results in stenosis, it may cause a fixed upper airway obstruction (figure 4) or a variable extrathoracic or intrathoracic obstruction (figure 4) depending on whether it is located above (extrathoracic) or below (intrathoracic) the thoracic inlet (level of the supra-sternal notch). In a fixed upper airway obstruction, there is flattening of the inspiratory and expiratory limbs of the flow volume loop. A variable extrathoracic obstruction causes flattening of the inspiratory portion of the flow volume loop, while a variable intrathoracic obstruction causes flattening of the expiratory portion of the loop. Spirometry commonly indicates restrictive ventilatory dysfunction. At least 50% of patients have concurrent obstructive airways disease, evidenced by a reduced ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC). [2, 68] Airway hyperreactivity assessed by methacholine challenge test occurs in 5-83% of patients. [47, 68]

**9. Bronchoscopy**

**10. Treatment**

The diagnosis of sarcoidosis is confirmed by histologic evidence of non-caseating, epitheliod granulomas. Tissue is obtained from the upper airways by direct nasopharyngoscopy. Transbronchial and/or mucosal biopsies of the lower airways may be obtained by bronchoco‐

Airways Disease in Sarcoidosis http://dx.doi.org/10.5772/55010 155

There are no controlled studies that examine the variety of therapeutic agents, which are purported to be effective in the treatment of sarcoidosis. There is consensus by experienced physicians that corticosteroids are the most efficacious medication. None of the other therapies share this favorable level of support. Oral corticosteroids are given in the smallest possible dose to limit their adverse effects. Since upper airways obstruction occurs in chronic sarcoi‐ dosis, 'steroid-sparring' medications may be administered simultaneously to reduce the corticosteroid dose that would be needed if it is given for many months. Hydroxychloroquine has been used with some success for cutaneous sarcoidosis. [69] Minocycline is also effective for the treatment of skin lesions. [70, 71] Minocycline appears to inhibit metalloproteinases,

The treatment of sinus and nasal sarcoidosis should be tailored to the specific organ system or systems involved and to the extent of disease. [14, 16] Isolated sinonasal disease can be treated by topical corticosteroids and/or intra-lesional steroid injections. [73] Nasal irrigations and emollients may be used to ameliorate nasal crusting. Siltzbach and Teirstein used chloroquine to treat 14 pataients with intrathoracic and cutaneous sarcoidosis. All of the patients showed relative improvement in their cutaneous lesions and most exhibited radiographic improve‐ ment of their intrathoracic disease. Johns and colleagues used hydroxychloroquine, a drug with less ocular toxicity, to treat mucosal lesions. [74] Patients taking hydroxychloroquine must have an ophthalmic exam every 6 months. Hassid reported a patient with biopsy-proven sarcoidosis of the paranasal sinuses who was successfully treated with hydroxychloroquine 200 mg orally, twice daily for one month and 200 mg per day for an additional 7 months. [75] Despite these results, the overall response rate for antimalarial drugs is probably less than 50% [76] and the drugs are often reserved for patients with cutaneous or sinonasal sarcoidosis, in

Methotrexate may also be used for the treatment of cutaneous sarcoidosis. In several case reports, skin lesions improved in patients who were treated with methotrexate 10 mg to 15 mg per week. [77] Although azathioprine has been commonly used as a corticosteroidsparing agent for many forms of sarcoidosis, it has rarely been reported for the treat‐ ment of skin sarcoidosis. [7] Tumor necrosis factor-a (TNF-a) antagonists have been reported to be useful in the treatment of sarcoidosis, including cutaneous sarcoidosis. [78] Inflixamab appears to be the most efficacious of the biologics. It may be especially useful

scopy, the diagnostic procedure of choice for sarcoidosis.

angiogenesis, apoptosis and in vitro granuloma formation. [68, 72]

whom the response to treatment can be easily observed. [76]

in the treatment of lupus pernio. [78]

**Figure 4.** Sarcoidosis patient with "honeycomb lung".

TLC = Total Lung Capacity, RV = Residual Volume

Adapated with permission from Kavuru et al…Essentials of Pulmonary and Critical care Medicine. 5th Edition. Philadel‐ phia. Lippincott, Williams and Wilkins, 2005.

**Figure 5.** Flow volume loops demonstrating various types of airways obstruction.

### **9. Bronchoscopy**

Spirometry commonly indicates restrictive ventilatory dysfunction. At least 50% of patients have concurrent obstructive airways disease, evidenced by a reduced ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC). [2, 68] Airway hyperreactivity

Adapated with permission from Kavuru et al…Essentials of Pulmonary and Critical care Medicine. 5th Edition. Philadel‐

assessed by methacholine challenge test occurs in 5-83% of patients. [47, 68]

**Figure 4.** Sarcoidosis patient with "honeycomb lung".

154 Sarcoidosis

TLC = Total Lung Capacity, RV = Residual Volume

**Figure 5.** Flow volume loops demonstrating various types of airways obstruction.

phia. Lippincott, Williams and Wilkins, 2005.

The diagnosis of sarcoidosis is confirmed by histologic evidence of non-caseating, epitheliod granulomas. Tissue is obtained from the upper airways by direct nasopharyngoscopy. Transbronchial and/or mucosal biopsies of the lower airways may be obtained by bronchoco‐ scopy, the diagnostic procedure of choice for sarcoidosis.

### **10. Treatment**

There are no controlled studies that examine the variety of therapeutic agents, which are purported to be effective in the treatment of sarcoidosis. There is consensus by experienced physicians that corticosteroids are the most efficacious medication. None of the other therapies share this favorable level of support. Oral corticosteroids are given in the smallest possible dose to limit their adverse effects. Since upper airways obstruction occurs in chronic sarcoi‐ dosis, 'steroid-sparring' medications may be administered simultaneously to reduce the corticosteroid dose that would be needed if it is given for many months. Hydroxychloroquine has been used with some success for cutaneous sarcoidosis. [69] Minocycline is also effective for the treatment of skin lesions. [70, 71] Minocycline appears to inhibit metalloproteinases, angiogenesis, apoptosis and in vitro granuloma formation. [68, 72]

The treatment of sinus and nasal sarcoidosis should be tailored to the specific organ system or systems involved and to the extent of disease. [14, 16] Isolated sinonasal disease can be treated by topical corticosteroids and/or intra-lesional steroid injections. [73] Nasal irrigations and emollients may be used to ameliorate nasal crusting. Siltzbach and Teirstein used chloroquine to treat 14 pataients with intrathoracic and cutaneous sarcoidosis. All of the patients showed relative improvement in their cutaneous lesions and most exhibited radiographic improve‐ ment of their intrathoracic disease. Johns and colleagues used hydroxychloroquine, a drug with less ocular toxicity, to treat mucosal lesions. [74] Patients taking hydroxychloroquine must have an ophthalmic exam every 6 months. Hassid reported a patient with biopsy-proven sarcoidosis of the paranasal sinuses who was successfully treated with hydroxychloroquine 200 mg orally, twice daily for one month and 200 mg per day for an additional 7 months. [75] Despite these results, the overall response rate for antimalarial drugs is probably less than 50% [76] and the drugs are often reserved for patients with cutaneous or sinonasal sarcoidosis, in whom the response to treatment can be easily observed. [76]

Methotrexate may also be used for the treatment of cutaneous sarcoidosis. In several case reports, skin lesions improved in patients who were treated with methotrexate 10 mg to 15 mg per week. [77] Although azathioprine has been commonly used as a corticosteroidsparing agent for many forms of sarcoidosis, it has rarely been reported for the treat‐ ment of skin sarcoidosis. [7] Tumor necrosis factor-a (TNF-a) antagonists have been reported to be useful in the treatment of sarcoidosis, including cutaneous sarcoidosis. [78] Inflixamab appears to be the most efficacious of the biologics. It may be especially useful in the treatment of lupus pernio. [78]

The indication for surgical intervention of sinonasal granulomatous lesions is controversial.

embolectomy catheter to dilate multiple bronchial stenoses under direct vision. [86] The six patients who underwent the procedure were symptomatic and refractory to corticosteroids. All of them obtained subjective symptomatic benefit from the dilatation. Three of the patients required repeated dilatation on a long-term basis. Complications from the procedure were minimal. Collectively, these studies suggest that bronchial dilatation is a safe option for

Airways Disease in Sarcoidosis http://dx.doi.org/10.5772/55010 157

The majority of patients with sarcoidosis improve with therapy. However, 10-30% of patients develop progressive pulmonary fibrosis, which may result in advanced airways disease such as bronchiectasis, bullae and cavitation. Rarely, patients with bronchiectasis will improve with corticosteroids, antibiotics and/or nonsteroidal anti-inflammatory medications. [87] If patients do respond, it is generally short-lived. Bullectomies performed for bullous sarcoidosis may improve pulmonary function and symptoms. [57, 58] Surgical resection of the cavity and removal of the fungus ball is the mainstay of treatment for aspergilloma(s). [88] The primary indication for resection is recurrent hemoptysis. Bronchial artery embolization is modestly effective in inoperable patients. [89] Taken together, advanced involvement in sarcoidosis is seldom responsive to medical therapy, moderately responsive to surgical therapy depending on the type of underlying disease and has an ominous prognosis. Finally, sarcoidosis patients with fibrotic lung disease and/or airways dysfunction often develop pulmonary hypertension,

Sarcoidosis is a chronic granulomatous disease of undetermined etiology that can involve any organ system within the body. Greater than 90% of patients with sarcoidosis have interstitial lung disease. [2] But the upper and lower respiratory tract is also affected. Sarcoidosis is one of a few interstitial lung diseases that involves the entire respiratory tract; beginning at the

Although many patients are asymptomatic, most complain of dyspnea, cough and/or wheez‐ ing, Patients with sarcoidosis of the upper respiratory tract present with a variety of symptoms, which are primarily determined by the anatomic location of the granulomatous inflammation and/or scarring that may result from chronic disease. The diagnosis of upper or lower

Computed tomography (CT), the imaging method of choice for sarcoidosis of the upper and lower respiratory tract, may demonstrate lesions within the sinonasal tract, larynx and trachea, large and small airways or parenchyma. It may also reveal mediastinal and/or hilar lympha‐

The physiology of airways obstruction depends on the location of the obstruction (intrathoracic or extrathoracic) and whether it is fixed or variable within the respiratory cycle. Granuloma‐ tous involvement of the larynx results in a fixed upper airway obstruction. Tracheal sarcoidosis may cause a fixed upper airway obstruction, or a variable extrathoracic or intrathoracic

sarcoidosis patients with stenoses who are refractory to systemic corticosteroids.

which often has an unfavorable prognosis.

nose and ending at the terminal bronchioles.

respiratory tract disease is frequently ascertained by bronchoscopy.

**11. Summary**

denopathy.

While surgery may reduce symptoms, it does not eradicate or prevent recurrence of disease. [14, 17, 79] Neville and associates evaluated 34 patients with sarcoidosis of the upper respira‐ tory tract, [9] 3 of whom, underwent submucous resection. In 2 of 3 patients the resection was complicated by nasal septal perforation. Aubart and colleagues operated on 7 patients. [17] Nasal and sinus involvement recurred in all of them and sinus symptoms worsened in 1 patient after surgery. But two additional studies suggest that endoscopic sinus surgery may have a therapeutic role in patients with nasal obstruction or chronic sinusitis caused by anatomic blockage from sinonasal sarcoidosis. [18, 80] Removal of the obstructing lesion(s) may facilitate improved sinonasal hygiene by permitting endoscopic debridement, nasal irrigation and topical administration of medicines into the sinonasal tract. Surgical intervention should not be used to treat patients with symptoms related to crusting, atrophy or bleeding. While surgery may improve one's quality of life by relieving severe symptoms and may even reduce the need for oral steroids, it is almost never curative.

Laryngeal sarcoidosis may cause life-threatening upper airway obstruction. As a result, early diagnosis and proper management is essential. The treatment of laryngeal sarcoidosis depends on the severity of the symptoms. Asymptomatic patients do not require therapy. [5, 19, 81] But close monitoring is warranted. It may be difficult to assess the efficacy of various treatment modalities because spontaneous remissions of disease punctuate the natural evolution of sarcodosis. [51, 67] Systemic corticosteroids are the mainstay of treatment for laryngeal sarcoidosis, especially for impending laryngeal obstruction. [1, 10] Methotrexate has been used with some success in the treatment of laryngeal sarcoidosis. One patient with granulomatous laryngitis responded to treatment with azathioprine. Intra-lesional steroid injections of the larynx for selected patients with well-circumscribed disease is modestly effective. [5, 21] When the airway is compromised and stridor is present, emergent tracheostomy should be per‐ formed. [21] Tracheostomy may also be an appropriate for patients who develop marked adverse effects from systemic corticosteroids. [82] Tracheostomy is often used as a temporizing measure until corticosteroids are able to effectively reduce granulomatous inflammation. Surgical intervention for laryngeal sarcoidosis is effective for patients with well-localized, life threatening lesions. [5] Typically, the goals of surgery are to create an adequate airway, avoid aspiration, avoid tracheostomy and preserve the voice. [5, 83] Low-dose external beam radiation therapy (3000 rads during 6 weeks) has been utilized in selected patients. [5, 84] It is generally reserved for patients in whom intra-lesional steroids or local excision of granulom‐ atous tissue are not feasible and/or in those who are refractory to or cannot tolerate systemic corticosteroids. [5, 82]

Tracheal involvement in sarcoidosis is limited to the description of tracheal dystonia [29] and tracheal stenosis. [29, 30] Brandstetter and colleagues used high-dose systemic corticosteriods to treat a patient with tracheal stenosis. The patient failed to stabilize with the treatment but ultimately underwent successful bronchoscopic tracheal dilatation. [30] Tracheal stents have been used with limited success for tracheobronchial obstruction in pediatric patients. [85]

Patients with bronchostenosis respond poorly to treatment with systemic corticosteroids. [33, 37, 46, 47, 53] Fouty and associates used a flexible fiberoptic bronchoscope and a Fogarty embolectomy catheter to dilate multiple bronchial stenoses under direct vision. [86] The six patients who underwent the procedure were symptomatic and refractory to corticosteroids. All of them obtained subjective symptomatic benefit from the dilatation. Three of the patients required repeated dilatation on a long-term basis. Complications from the procedure were minimal. Collectively, these studies suggest that bronchial dilatation is a safe option for sarcoidosis patients with stenoses who are refractory to systemic corticosteroids.

The majority of patients with sarcoidosis improve with therapy. However, 10-30% of patients develop progressive pulmonary fibrosis, which may result in advanced airways disease such as bronchiectasis, bullae and cavitation. Rarely, patients with bronchiectasis will improve with corticosteroids, antibiotics and/or nonsteroidal anti-inflammatory medications. [87] If patients do respond, it is generally short-lived. Bullectomies performed for bullous sarcoidosis may improve pulmonary function and symptoms. [57, 58] Surgical resection of the cavity and removal of the fungus ball is the mainstay of treatment for aspergilloma(s). [88] The primary indication for resection is recurrent hemoptysis. Bronchial artery embolization is modestly effective in inoperable patients. [89] Taken together, advanced involvement in sarcoidosis is seldom responsive to medical therapy, moderately responsive to surgical therapy depending on the type of underlying disease and has an ominous prognosis. Finally, sarcoidosis patients with fibrotic lung disease and/or airways dysfunction often develop pulmonary hypertension, which often has an unfavorable prognosis.

### **11. Summary**

The indication for surgical intervention of sinonasal granulomatous lesions is controversial. While surgery may reduce symptoms, it does not eradicate or prevent recurrence of disease. [14, 17, 79] Neville and associates evaluated 34 patients with sarcoidosis of the upper respira‐ tory tract, [9] 3 of whom, underwent submucous resection. In 2 of 3 patients the resection was complicated by nasal septal perforation. Aubart and colleagues operated on 7 patients. [17] Nasal and sinus involvement recurred in all of them and sinus symptoms worsened in 1 patient after surgery. But two additional studies suggest that endoscopic sinus surgery may have a therapeutic role in patients with nasal obstruction or chronic sinusitis caused by anatomic blockage from sinonasal sarcoidosis. [18, 80] Removal of the obstructing lesion(s) may facilitate improved sinonasal hygiene by permitting endoscopic debridement, nasal irrigation and topical administration of medicines into the sinonasal tract. Surgical intervention should not be used to treat patients with symptoms related to crusting, atrophy or bleeding. While surgery may improve one's quality of life by relieving severe symptoms and may even reduce the need

Laryngeal sarcoidosis may cause life-threatening upper airway obstruction. As a result, early diagnosis and proper management is essential. The treatment of laryngeal sarcoidosis depends on the severity of the symptoms. Asymptomatic patients do not require therapy. [5, 19, 81] But close monitoring is warranted. It may be difficult to assess the efficacy of various treatment modalities because spontaneous remissions of disease punctuate the natural evolution of sarcodosis. [51, 67] Systemic corticosteroids are the mainstay of treatment for laryngeal sarcoidosis, especially for impending laryngeal obstruction. [1, 10] Methotrexate has been used with some success in the treatment of laryngeal sarcoidosis. One patient with granulomatous laryngitis responded to treatment with azathioprine. Intra-lesional steroid injections of the larynx for selected patients with well-circumscribed disease is modestly effective. [5, 21] When the airway is compromised and stridor is present, emergent tracheostomy should be per‐ formed. [21] Tracheostomy may also be an appropriate for patients who develop marked adverse effects from systemic corticosteroids. [82] Tracheostomy is often used as a temporizing measure until corticosteroids are able to effectively reduce granulomatous inflammation. Surgical intervention for laryngeal sarcoidosis is effective for patients with well-localized, life threatening lesions. [5] Typically, the goals of surgery are to create an adequate airway, avoid aspiration, avoid tracheostomy and preserve the voice. [5, 83] Low-dose external beam radiation therapy (3000 rads during 6 weeks) has been utilized in selected patients. [5, 84] It is generally reserved for patients in whom intra-lesional steroids or local excision of granulom‐ atous tissue are not feasible and/or in those who are refractory to or cannot tolerate systemic

Tracheal involvement in sarcoidosis is limited to the description of tracheal dystonia [29] and tracheal stenosis. [29, 30] Brandstetter and colleagues used high-dose systemic corticosteriods to treat a patient with tracheal stenosis. The patient failed to stabilize with the treatment but ultimately underwent successful bronchoscopic tracheal dilatation. [30] Tracheal stents have been used with limited success for tracheobronchial obstruction in pediatric patients. [85] Patients with bronchostenosis respond poorly to treatment with systemic corticosteroids. [33, 37, 46, 47, 53] Fouty and associates used a flexible fiberoptic bronchoscope and a Fogarty

for oral steroids, it is almost never curative.

156 Sarcoidosis

corticosteroids. [5, 82]

Sarcoidosis is a chronic granulomatous disease of undetermined etiology that can involve any organ system within the body. Greater than 90% of patients with sarcoidosis have interstitial lung disease. [2] But the upper and lower respiratory tract is also affected. Sarcoidosis is one of a few interstitial lung diseases that involves the entire respiratory tract; beginning at the nose and ending at the terminal bronchioles.

Although many patients are asymptomatic, most complain of dyspnea, cough and/or wheez‐ ing, Patients with sarcoidosis of the upper respiratory tract present with a variety of symptoms, which are primarily determined by the anatomic location of the granulomatous inflammation and/or scarring that may result from chronic disease. The diagnosis of upper or lower respiratory tract disease is frequently ascertained by bronchoscopy.

Computed tomography (CT), the imaging method of choice for sarcoidosis of the upper and lower respiratory tract, may demonstrate lesions within the sinonasal tract, larynx and trachea, large and small airways or parenchyma. It may also reveal mediastinal and/or hilar lympha‐ denopathy.

The physiology of airways obstruction depends on the location of the obstruction (intrathoracic or extrathoracic) and whether it is fixed or variable within the respiratory cycle. Granuloma‐ tous involvement of the larynx results in a fixed upper airway obstruction. Tracheal sarcoidosis may cause a fixed upper airway obstruction, or a variable extrathoracic or intrathoracic obstruction, depending on whether the lesion is located above (extrathoracic) or below (intrathoracic) the thoracic inlet (level of the supra-sternal notch).

[7] Marchell, R. M, & Judson, M. A. Cutaneous sarcoidosis. Semin Respir Crit Care Med.

Airways Disease in Sarcoidosis http://dx.doi.org/10.5772/55010 159

[8] Maples, C. J, & Counselman, F. L. Lupus pernio. J Emerg Med. (2007). Aug;, 33(2),

[9] Neville, E, Mills, R. G, & James, D. G. Sarcoidosis of the upper respiratory tract and

[10] Polychronopoulos, V. S, & Prakash, U. B. Airway involvement in sarcoidosis. Chest. (2009). Nov;A review article that discusses airway involvement in sarcoidosis.,

[11] Deshazo, R. D, Brien, O, Justice, M. M, & Pitcock, W. K. J. Diagnostic criteria for sar‐ coidosis of the sinuses. J Allergy Clin Immunol. (1999). May;103(5 Pt 1):789-95.

[12] Fergie, N, Jones, N. S, & Havlat, M. F. The nasal manifestations of sarcoidosis: a re‐ view and report of eight cases. J Laryngol Otol. (1999). Oct;, 113(10), 893-8.

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Patients with pulmonary sarcoidosis may exhibit obstructive, restrictive, restrictive and obstructive, or gas transfer abnormalities. Corticosteroids are the mainstay of therapy for upper respiratory tract disease. However, other immunosuppressive treatments may be effective for the treatment of skin and sinonasal sarcoidosis. Patients with endobronchial or tracheal stenoses who are refractory to steroid therapy may derive some benefit from me‐ chanical dilatation of the airways. [86] Surgical intervention may be required for treatment of bullous sarcoidosis and aspergilloma. [57, 58]

### **Author details**

Adam S. Morgenthau

Address all correspondence to: adam.morgenthau@mssm.edu

The Mount Sinai School of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York, NY, USA

Dr. Morgenthau discloses no conflicts of interest.

### **References**


[7] Marchell, R. M, & Judson, M. A. Cutaneous sarcoidosis. Semin Respir Crit Care Med. (2010). Aug;, 31(4), 442-51.

obstruction, depending on whether the lesion is located above (extrathoracic) or below

Patients with pulmonary sarcoidosis may exhibit obstructive, restrictive, restrictive and obstructive, or gas transfer abnormalities. Corticosteroids are the mainstay of therapy for upper respiratory tract disease. However, other immunosuppressive treatments may be effective for the treatment of skin and sinonasal sarcoidosis. Patients with endobronchial or tracheal stenoses who are refractory to steroid therapy may derive some benefit from me‐ chanical dilatation of the airways. [86] Surgical intervention may be required for treatment of

The Mount Sinai School of Medicine, Department of Medicine, Division of Pulmonary,

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Address all correspondence to: adam.morgenthau@mssm.edu

Critical Care and Sleep Medicine, New York, NY, USA

Dr. Morgenthau discloses no conflicts of interest.

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**Chapter 7**

**Physiological Manifestation in Pulmonary Sarcoidosis**

Sarcoidosis is a granulomatous disease involving multiple organs with unknown cause. More than 90% of patients with sarcoidosis have lung disease [1–3]. However, respiratory function in patients with sarcoidosis often remains normal, even when pulmonary parenchymal involvement is extensive. Not only the lung parenchyma but also the lung airways are involved, which sometimes makes it difficult to evaluate the relationship between functional

Respiratory function impairment in sarcoidosis has not been considered to be a major concern in either clinical or basic research. However, the marked restrictive ventilatory impairment in sarcoidosis with end-stage pulmonary fibrosis is a serious problem in clinical practice.

Obstructive disease is another manifestation of respiratory function impairment in sarcoido‐ sis that is sometimes associated with the end-stage fibrosis of sarcoidosis, with marked reduction of vital capacity and total lung capacity. However, obstructive ventilatory impairment also appears without restrictive disease of sarcoidosis, especially in the early

This chapter will review the functional impairment in patients with pulmonary sarcoidosis, especially restrictive and obstructive ventilatory impairments, taking the histological back‐

Restrictive impairment is mainly caused by extensive fibrosis secondary to sarcoid granulomas

and reproduction in any medium, provided the original work is properly cited.

© 2013 Watanabe; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

or by interstitial pneumonia coexistent with pulmonary sarcoidosis.

Kentaro Watanabe

**1. Introduction**

stage of sarcoidosis [4–6].

ground into consideration.

**2. Restrictive impairment**

http://dx.doi.org/10.5772/55012

Additional information is available at the end of the chapter

impairment and morphological/imaging patterns.

