Sarcoidosis is a granulomatous disease involving mainly the lungs and lymphatic system, but also eyes and skin.
Etiology and pathogenesis
Although the exact etiology and pathogenesis of sarcoidosis are unclear and need further research, it is currently believed that sarcoidosis is a granulomatous disease resulting from an enhanced local Th1/Th17 cellular immune response in the affected organs due to stimulation of specific environmental exposures in genetically susceptible individuals,
Pathology
The characteristic pathological changes of sarcoidosis are non-caseous, necrotizing, epithelioid granuloma, mainly composed of highly differentiated mononuclear phagocytes (epithelial cells and giant cells) and lymphocytes. Giant cells can have inclusions such as Schauman bodies and asteroid bodies. The center of the granuloma is mainly composed of CD4+ lymphocytes, while the periphery is mainly composed of CD8+ lymphocytes. Sarcoidosis granulomas either subside or develop into fibrosis. In the lungs, 75% of granulomas are distributed along lymphatic vessels, close to or located in the bronchial vascular sheath, subpleural region, or interlobular septa. Blood vessel involvement in more than half of granulomas has been found in open lung biopsy or autopsy. Besides, involvement in or around the airways is also common.
Clinical manifestations
The clinical course of sarcoidosis varies, which is related to the speed of onset, different organ involvements, and activity of granulomas, as well as race and region.
Acute sarcoidosis
Acute sarcoidosis (Lofgren syndrome) is manifested by bilateral hilar lymphadenopathy, arthritis, and erythema nodosum, often accompanied by fever, myalgia, and malaise. 85% of patients resolve spontaneously within one year.
Subacute/chronic sarcoidosis
About 50% of sarcoidosis is asymptomatic and is incidentally found in physical examination or chest x-ray.
About 1/3 of patients may have non-specific manifestations, such as fever, emaciation, asthenia, malaise, and diaphoresis.
More than 90% of sarcoidosis involves the lungs. Clinical manifestations are insidious, with cough, thoracodynia, dyspnea, airway hyperresponsiveness, or wheezing.
Extrathoracic sarcoidosis includes involvements of lymph nodes, skin, eyes, heart, and endocrine.
Auxiliary examination
Chest x-ray
More than 90% of patients have abnormal chest x-ray. Chest x-ray is sensitive for diagnosis. Bilateral hilar lymphadenopathy (BHL), with or without right paratracheal lymphadenopathy, is the most common sign. Clinically, sarcoidosis is usually staged based on the posteroanterior chest x-ray radiograph, and this staging is related to the natural remission of the disease.
Table 1 Clinical stages of sarcoidosis
Figure 1 Sarcoidosis on x-ray
Chest x-ray shows bilateral hilar lymphadenopathy.
Chest CT/HRCT
The typical manifestation of HRCT is small nodules distributed along the bronchovascular bundle and interlobular septa, which can fuse. Other abnormalities include ground-glass opacities, irregular linear opacities, honeycomb lung, traction bronchiectasis, and distortion or deformation of blood vessels or bronchi. The lesions mostly invade the upper lobe, and the basal lung is relatively normal. The pretracheal, paratracheal, paraaortic, and subcarinal lymphadenopathy can be seen.
Figure 2 Sarcoidosis on CT
Chest HRCT shows many small nodules distributed along the lymphatic vessels, in the peribronchovascular interstitium, interlobular septa, and subpleural regions; and mediastinal and hilar lymphadenopathy.
Radionuclide imaging
The uptake of 67Ga by active macrophages in granulomas is significantly increased, and granulomatous lesions can be displayed by 67Ga. Typical lesion shows panda sign (visualized nasal mucosa, bilateral lacrimal glands, and parotid glands) and lambda (λ) sign (visualized right paratracheal area and bilateral hilar lymph nodes), without diagnostic specificity. 18F-FDG PET can also be used for the diagnosis of sarcoidosis, can detect more occult lesions, and can help evaluate cardiac sarcoidosis. However, 18F-FDG PET cannot distinguish sarcoidosis from malignant tumors and pulmonary tuberculosis, and other examinations are required.
Pulmonary function test
More than 80% of mild patients have normal pulmonary function. Moderate patients with abnormal pulmonary function account for 40% - 70%, and the characteristic changes are restrictive ventilation dysfunction, reduced diffusion capacity, and deoxygenation. More than 1/3 of patients also have airflow limitation.
Fiberoptic bronchoscopy and bronchoalveolar lavage
Bronchoscopy can show widened tracheal carina caused by subcarinal lymphadenopathy and mucosal nodules caused by involvement of the tracheobronchial mucosa. BALF examination mainly shows an increase in lymphocytes and an increase in the CD4/CD8 ratio (>3.5). Sarcoidosis can be diagnosed by transbronchoscopic biopsy (TBB), transbronchoscopic lung biopsy (TBLB), and endobronchial ultrasound guided tranbronchial needle aspiration (EBUS-TBNA). These examinations have a high diagnostic rate and low risk, and have been an important diagnostic method for pulmonary sarcoidosis. Mediastinoscopy or surgical lung biopsy is generally not required.
Blood test
Angiotensin converting enzyme (ACE) is produced by epithelioid cells of sarcoidosis granulomas. The serum ACE level reflects the granuloma load in the body and can assist in judgment of the activity of the disease. However, due to the lack of sufficient sensitivity and specificity, it cannot be used as a diagnostic indicator. Other indicators of disease activity include serum soluble interleukin-2 receptor (sIL-2R) and hypercalcemia.
Tuberculin test
No or weak reaction to the tuberculin skin test of PPD 5TU is a characteristic of sarcoidosis and can be used to differentiate tuberculosis from sarcoidosis.
Diagnosis
The diagnosis of sarcoidosis should meet three conditions:
- Clinical and chest imaging manifestations indicating sarcoidosis
- Presence of non-caseous necrotizing epithelial granuloma confirmed by biopsy
- Exclusion of other diseases
After the diagnosis is established, it is also necessary to determine the range, stage, and activity. Acute onset, marked clinical symptoms, rapid progression, involvement of important organs, and increased serum ACE suggest active sarcoidosis.
Differential diagnosis
Hilar lymphatic tuberculosis
There are young patients, mostly positive tuberculin test, generally unilateral hilar lymph node enlargement, sometimes accompanied by calcification, and primary pulmonary lesions. CT shows necrosis in the central lymph nodes.
Lymphoma
Lymphoma is often characterized by fever, emaciation, and anemia. Lymph nodes in the upper mediastinum and subcarinal areas are often involved, mostly unilaterally or bilaterally asymmetrically enlarged, and the lymph nodes may be fused.
Hilar metastatic tumor
Metastasis of lung cancer and extrapulmonary tumor to hilar lymph nodes presents corresponding symptoms and signs. Further examination of suspected primary lesions can assist in identification.
Other granulomatous diseases
In hypersensitivity pneumonitis, berylliosis, silicosis, and granulomas caused by infectious and chemical factors, comprehensive analysis of clinical data and related examinations is helpful for differentiation from sarcoidosis.
Treatment
Half of sarcoidosis patients are asymptomatic, 60% - 70% of sarcoidosis patients can relieve spontaneously, and chronic sarcoidosis accounts for 10% - 30%. Therefore, no treatment is required for inactive and asymptomatic sarcoidosis, but follow-up observation is required.
If there are marked symptoms, significant pulmonary function abnormalities, and pulmonary parenchymal lesions, as well as extrapulmonary manifestations, especially involvement of the heart, nervous system, liver, and spleen, systemic glucocorticoid treatment is required. For pulmonary sarcoidosis, the treatment regimen is prednisone (or other hormones) 0.5mg/(kg·d) or 20 - 40mg/d initially, the dose is gradually reduced to 5 -10mg/d in 2 - 4 weeks, and the total course of treatment is 6 - 24 months. The recurrence rate of sarcoidosis is 16% - 74%. In patients with recurrence tendency, the dose of hormones should be appropriately increased. When glucocorticoids are not tolerated or ineffective, other immunosuppressants such as methotrexate, azathioprine, leflunomide, and mycophenolate mofetil, and biological agents such as infliximab and adalimumab, can be considered. After the treatment of sarcoidosis is completed, a follow-up every 3-6 months is required for at least 3 years or until the condition is stable.
Prognosis
The course and prognosis of sarcoidosis vary greatly. The spontaneous remission of stage I, II, and III pulmonary sarcoidosis is 55% - 90%, 40% - 70%, 10% - 20%, respectively. Acute sarcoidosis has great prognosis after treatment or spontaneous remission, while chronic progressive sarcoidosis has poor prognosis due to multiple organ dysfunction and extensive pulmonary fibrosis. The overall mortality is 1% - 5%. The death is often caused by respiratory insufficiency or involvement of the heart and central nervous system, and 75% of deaths are related to progressive pulmonary sarcoidosis. However, prognostic indicators for severe, chronic, progressive, pulmonary sarcoidosis have not been determined yet.