Epidemiology

Sarcoidosis is worldwide in its distribution, but it is most frequently recognized in developed countries where adequate diagnostic facilities are available. Although all races are affected, series in the USA generally show that the disease is more prevalent in blacks than in whites. It has also been noted that the prevalence of sarcoidosis in black populations of Africa and South America is less than what has been observed in the African American population.^7–9 Both sexes are affected, with the overall frequency showing a very slight excess of females (approximately 60%). Sarcoidosis is a disease of young adults, with almost three-fourths of cases occurring in those younger than 40 years of age. Children may be affected, but this is uncommon.^6–10 The clinical course of childhood sarcoidosis is often atypical; that is, there is less frequent pulmonary involvement and more frequent extrathoracic disease.^11,12 A recent study of 46 caucasian children from Denmark reported the four most frequent presenting symptoms to be erythema nodosum (22%), iridocyclitis (22%), peripheral lymphadenopathy (15%), and cutaneous sarcoidosis (7%). Overall, a good prognosis was observed. Moreover, erythema nodosum was generally associated with good outcomes while central nervous system (CNS) involvement was associated with a poor prognosis.¹³ These children must be differentiated from children with juvenile rheumatoid arthritis and those with familial juvenile systemic granulomatosis^14–17 because of the similarity of ocular and articular involvement. Many cases of familial juvenile systemic granulomatosis are misdiagnosed as childhood sarcoidosis.¹⁸

Etiology and pathogenesis

The etiology of sarcoidosis is unknown. Multiple etiologies have been proposed, including a variety of infectious agents, allergy to pine pollen and peanut dust, chewing pine pitch, and hypersensitivity to chemicals such as beryllium or zirconium. To date, there is no conclusive evidence to implicate any of these as an etiologic agent. Familial studies and human leukocyte antigen (HLA) typing have suggested a possible genetic predisposition, but these studies are far from conclusive.¹⁹ A cooperative multicenter study, A Case Control Etiologic Study of Sarcoidosis (ACCESS), enrolled 736 biopsy-confirmed cases from 10 centers in the USA and suggested a genetic predisposition for sarcoidosis, presenting evidence for the allelic variation at the HLA-DRB1 locus as a contributing factor to the disease. The most significant finding was the relationship between DRB1*0401 and eye involvement (P ≤ 0.0008; odds ratio (OR) 3.49) in the study population. Although only 2% of blacks had a DRB1*0401 allele, a similar OR was present in both blacks and whites.¹⁹

Patients with sarcoidosis are characterized by depression of delayed-type hypersensitivity, reflected by T-cell anergy, and skin tests that are often negative. Peripheral blood lymphocytes from patients with sarcoidosis show diminished responses to mitogens.

Bronchoalveolar lavage has enabled investigators to determine the immunologic events at the area of active disease in the lungs. These studies have shown entirely different results from peripheral blood lymphocytes. In the lungs, there is an excess of helper T lymphocytes (CD4+). These activated helper T cells spontaneously secrete lymphokines, including interleukin-2 (IL-2), and will polyclonally activate B cells to produce immunoglobulins. These studies have been interpreted to show that an active T-cell-driven immunologic response occurs at the target organ site and eventually leads to granuloma formation.^21,22 Studies of bronchoalveolar lavage fluids have suggested that macrophages may also play a role in the pathogenesis of pulmonary sarcoidosis by inducing changes in the pulmonary microvasculature.²³

Immunohistologic studies of biopsy tissue from patients with sarcoidosis have demonstrated the presence of cells of macrophage lineage and activated T cells in the granuloma. The vast majority of lymphocytes are T cells of the helper subset (CD4+) and express activation markers, including class II antigens and the IL-2 receptor.^24–26

Clinical features

The organs most frequently involved in sarcoidosis are the lungs, lymph nodes and spleen, skin, eyes, nervous system, and bones and joints^1,19,27–29 (Table 78.1).

Table 78.1 Organ system involvement in sarcoidosis

Investigations

Histology

Histologic confirmation (Table 78.2) is generally required to establish the diagnosis of sarcoid. The only clinical situation when diagnosis of sarcoidosis can be strongly considered reliably without biopsy is Löfgren syndrome (see below). Otherwise, biopsy should be done. Sites most often biopsied include the lungs, mediastinal lymph nodes, skin, peripheral lymph nodes, liver, and conjunctiva. Biopsy of clinically evident skin lesions or palpable lymph nodes is frequently performed because of the high yield and low morbidity. Fiberoptic bronchoscopy with transbronchial lung biopsy is positive in 80% of patients with intrapulmonary sarcoidosis. This procedure is routinely performed by pulmonary physicians and has a relatively low morbidity. The next step in such a scenario is cervical mediastinoscopy, which is both highly invasive and an expensive procedure. The requirement of general anesthesia further increases the chances of complications from the procedure. From the patient’s perspective it is important that further possibilities of minimally invasive techniques for the diagnosis of sarcoidosis are explored. Development of linear echoendoscopes and subsequent procedures (endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) ) has opened new diagnostic possibilities for sarcoidosis. Both techniques allow real-time monitoring of the needle. Several investigators have reported a high sensitivity of 72–85% for EBUS-TBNA and minimal complications. In a randomized control trial (RCT) Tremblay et al.⁴⁹ have shown that the diagnostic yield of EBUS-guided TBNA (95.8%) versus the conventional TBNA (73.1%) was 22.7% greater. Sensitivity and specificity were 60.9% and 100%, respectively, in the standard TBNA group, and 83.3% and 100%, respectively, in the EBUS-guided TBNA group (absolute increase in sensitivity of 22.5%). EUS-FNA was used for diagnosis of sarcoidosis and had a yield of 82% and sensitivity of 89–94% by assessing noncaseating granulomas in mediastinal nodes.⁵⁰ The liver biopsy is often positive in patients with sarcoidosis, but the finding of granulomatous lesions on liver biopsy must be interpreted with caution, as they can be produced by other disorders. Other potential biopsy sites include peripheral lymph nodes and minor salivary glands.

Table 78.2 Yield of different biopsy sites in the diagnosis of sarcoidosis

Conjunctival biopsies are positive in 25–57% of patients with histologically documented sarcoidosis. Variations in these reports are the result of whether clinically evident lesions are biopsied or whether a “blind” conjunctival biopsy is performed. However, the yield can be increased by techniques such as bilateral conjunctival biopsies and serial sectioning of the specimens, and careful inspection of the conjunctiva for any visibly evident nodules which can be biopsied. Transconjunctival lacrimal gland biopsy can also be used for histologic diagnosis, but the procedure is not performed routinely.^42,51

Immunology

The Kveim skin test was a simple, specific, outpatient skin test using human sarcoid tissue. It was positive in 78% of patients with sarcoidosis and was helpful in delineating multisystemic sarcoidosis from other granulomatous disorders. The antigen was a saline suspension of human sarcoid tissue prepared from the spleen of a patient suffering from active sarcoidosis. This material was injected intradermally, and the site inspected for nodule formation after 3–6 weeks. A palpable nodule was biopsied, and the finding of noncaseating granulomas on biopsy established the diagnosis of sarcoid.^19,52,53 Concerns about the injection of human tissue, with its potential for disease transmission, have essentially eliminated the use of the Kveim test.

Noninvasive tests

Multiple attempts have been made to find noninvasive tests that could be both sensitive and specific in the diagnosis of sarcoidosis. These have included measurement of serum calcium, urinary calcium, serum lysozyme, and serum immunoglobulins. Although all these may be abnormal in patients with sarcoid, they are nonspecific and nondiagnostic. The serum ACE level has been touted as a useful measurement in the diagnosis of sarcoidosis. The ACE level is frequently abnormal in patients with active sarcoidosis and appears to reflect the total-body granuloma content in such patients. As such, it may be useful in following patients with active sarcoid.^43,52,54 However, it is not diagnostic of sarcoidosis and appears to be of limited utility in the diagnostic dilemma of patients with possible sarcoid uveitis but a normal chest film.

For following patients with active intrapulmonary sarcoid, pulmonary function tests, particularly forced vital capacity, forced expiratory volume, and diffusing capacity, are far more useful. Changes in pulmonary function tests are often used to follow patients with sarcoidosis and to adjust the corticosteroid dosage.²⁷

Jabs and Johns⁵⁵ reported that over 80% of patients with ocular sarcoid had their ocular lesions at the time of diagnosis of sarcoidosis, and Hunter and Foster⁴⁸ reported that 3% of patients with uveitis were diagnosed as having sarcoid after the initial evaluation for a systemic disease revealed no diagnosable systemic disorder. Although patients who present with uveitis should be evaluated for sarcoid, repetitive workups appear to have limited value unless new symptoms arise.