The presentation of sarcoidosis depends on epidemiological factors such as age, sex and race, the duration of the disease and the sites of involvement. Asymptomatic presentations, erythema nodosum and hypercalcemia are more frequent in Europeans, while symptomatic and multivisceral presentations are more frequent in Afro-Americans [1–4, 9]. Overall, sarcoidosis is mostly revealed in the following circumstances: (i) respiratory symptoms, firstly persistant dry cough in around 30% cases, (ii) extrathoracic localizations, mainly peripheral lymph nodes, eyes or skin, (iii) constitutional symptoms such as fatigue (27%), weight loss (28%), fever (10–17%) or night sweats and (iv) erythema nodosum (3–44%) [1, 3, 4, 18]. Erythema nodosum is usually associated with bilateral intrathoracic lymphadenopathies defining "Löfgren's syndrome" which is a benign form of the disease. Constitutional symptoms, particularly asthenia, are often present and can be a disabling problem [18]. Finally, an incidental discovery of sarcoidosis in asymptomatic patients with chest X-ray aberrations is not uncommon (8–60%) [19].
Intrathoracic manifestations
Detailed occupational and environmental history is usually unremarkable and exposure to beryllium dusts and to drugs inducing granulomatosis must be excluded. As a general rule, no abnormality is audible at chest physical examination. By contrast, chest X-ray is abnormal at some point in 86–92% of cases and remains a key investigation for diagnosis [1, 2, 9, 19, 20]. Radiographic staging of sarcoidosis is based on the presence of lymphadenopathies and lung infiltration without or with fibrosis [3]. Lymphadenopathies are typically hilar, bilateral, symmetrical and non compressive, and often associated with right paratracheal and aortic-pulmonic window lymph node involvement [19, 20]. Lung infiltration is usually bilateral, symmetrical and diffuse but with a patent predominance for central regions and upper lobes. The pattern of infiltration is typically micronodular (diffuse punctiform opacities).
Stage I, the most frequent presentation, is defined as isolated intrathoracic lymphadenopathy, stage II as lymphadenopathy accompanied by lung infiltration and stage III as lone parenchymal infiltration. Stage IV refers to overt lung fibrosis. Typical stage I and II are highly reliable for diagnosing sarcoidosis, while stage III and IV are far less accurate [3]. This classification was established more than four decades ago but it still represents a major determinant of prognosis [19]. The probability of further spontaneous healing decreases as a function of initial radiographic stage (55–90% in stage I; 40–70% in stage II; 10–20% in stage III and 0% in stage IV) [3].
Pulmonary function tests typically demonstrate decreased volumes and CO diffusing capacity with functional alteration tending to be more frequent and marked from stage I to stage IV [20]. Using the criterion of forced expiratory volume in 1 sec (FEV1)/vital capacity (VC) ratio < 70%, airway obstruction is encountered in 5.7% of cases [21]. Airway obstruction has been recognized as a marker of poor prognosis including increased morbidity, higher frequency of respiratory symptoms and radiographic stage IV [22, 23].
Fiberoptic bronchoscopy yields granulomas by means of mucosal or transbronchial biopsy in 57–88% of cases [3, 24, 25]. Lymphocytosis in broncho-alveolar lavage (BAL) is observed in 90% of cases and a CD4+/CD8+ T lymphocyte ratio greater than 3.5 in half cases [24]. Transbronchial needle aspiration makes also possible valuable samplings of hilar and mediastinal lymph nodes [25].
Chest high resolution computed tomography (HRCT) has a better diagnosis accuracy than chest X-ray [19, 20]. The hallmark of pulmonary sarcoidosis are widespread micronodules with a typical perilymphangitic distribution and a predominance for the middle and upper parts of the lungs. However, HRCT is not always necessary when a confident diagnosis can be made from typical clinical and radiographic features. By contrast, HRCT makes compelling diagnostic contributions in tricky cases and in detecting complications of the lung disease. HRCT is also particularly useful in cases difficult to treat [26].
Extrathoracic manifestations
Apart from intrathoracic lymph nodes and lung, the most frequent sites of sarcoidosis involvement include peripheral lymph nodes, eyes, skin and liver, each being noted in about 10–25% of cases in most series [1–4, 9]. Virtually any organ may be affected by sarcoidosis but the frequency and degree of impairement is variable according to localizations. Overall, extrathoracic manifestations occur in about half of the cases and in this setting are associated with intrathoracic involvement in 80–90% cases. Extrathoracic localizations can be confined to one organ or be multiple and diversely combined.
Peripheral lymphadenopathies are easily palpable and their frequency varies between series up to 70%. They are asymptomatic, firm, of various size and every site of lymph nodes may be affected. Peripheral lymphadenopathies are readily accessible to biopsy. They can be localized in the abdomen where they are recognizable by abdominal echography, computed tomography (CT) or magnetic resonance imaging (MRI) and they can be associated with liver or splenic nodules or enlargement.
The frequency of ocular sarcoidosis is comprised between 10 and 50% according to published studies. This wide range is due to recruitment bias in series reported by ophtalmologists and to epidemiological factors with an increased incidence in Japanese patients [27]. Any part of the eye may be involved in sarcoidosis. Macroscopic nodules of the conjunctiva are seen in 6–40% of cases and allow evidence of granulomas in 67% of cases [27]. Anterior uveitis can be an initial, acute and symptomatic (red eyes, photophobia and blurred vision) manifestation but it can also be asymptomatic and have a chronic course justifying a systematic eye investigation including a slit lamp examination. Similarly, intermediate uveitis can be symptomatic or not. Posterior uveitis is encountered in up to 28% of cases with eye sarcoidosis and it may be associated with neurologic involvement. Optic neuropathy is very rare but it may provoke a rapid and definitive loss of vision in the absence of immediate and adequate systemic treatment. Lacrimal involvement may lead to sicca keratoconjonctivitis, while bilateral enlargement of lacrimal gland is unfrequent.
Skin manifestations of sarcoidosis are heterogeneous. Erythema nodosum is a non specific association of sarcoidosis realizing typically Löfgren's syndrome in the presence of bilateral hilar lymphadenopathy. The incidence of Löfgren's syndrome varies according to epidemiological factors (see "Epidemiology"). The frequency of specific skin manifestations of sarcoidosis ranges from 10 to 40% cases [28]. They appear at any stage of the disease and can remain strictly isolated in one third of cases [28]. The clinical picture of skin sarcoidosis is variegated: maculopapular lesions of various size, changes of old scars, lupus pernio, plaque formation, subcutaneous lesions etc. Skin lesions supply a plain and proper site for biopsy with the exception of erythema nodosum. Lesions of the face such as lupus pernio are very unpleasant and often linked with a longstanding evolution of sarcoidosis and osseous and sinonasal localizations. They are often difficult to control with treatments.
Liver involvement
while granulomas are found in up to 60–80% of liver biopsy specimens, abnormalities of biological tests, primarily cholestasis, are evidenced in only about 20% of cases. Clinical enlargement of the liver is far less frequent. Chronic intrahepatic cholestasis, hepatic dysfunction, cirrhosis and portal hypertension are all severe but rare complications of sarcoidosis.
Localizations of sarcoidosis in heart, central nervous system, larynx or kidney are less frequent but potentially serious.
Cardiac involvement of sarcoidosis appears to be much more frequent in Japanese population, particularly in females > 50 years, than in Europeans and Americans in which it concerns approximatively 5% of cases [29, 30]. It can occur at any point of time during the course of sarcoidosis. The left ventricular myocardium and, more specifically, the interventricular septum and the free left lateral wall are the most frequently involved structures in sarcoidosis. Main relevant signs include atrio-ventricular block, complete right bundle branch block (which is notably frequent and suggestive), ventricular hyperexcitability, ventricular tachycardia, left ventricular dysfunction and sudden death. The diagnosis of cardiac sarcoidosis is often a challenging issue for physicians. Serial electrocardiogram (ECG) during evolution survey, echocardiography, 24-h Holter monitoring of ECG, Thallium scan, MRI and and 18FDG PET can be helpful tools for diagnosis (29,30). Endomyocardial biopsy is theoretically the most confident mean to ascertain the diagnosis but in clinical practice it lacks sensitivity and it is an invasive procedure, which constitutes major limitations. Thus, the diagnosis of cardiac sarcoidosis usually relies on the conjunction of multiple arguments: (i) evidence of sarcoidosis, (ii) presence of cardiac abnormalities compatible with cardiac sarcoidosis and (iii) exclusion of any other cause of cardiac disease.
Any part of the nervous system can be involved in sarcoidosis with a frequency around 10% [31, 32]: meninges, central nervous system, cranial nerves and peripheral nerves. Aseptic meningitis can cause symptoms such as fever or headache and be associated with central nervous system manifestations or cranial neuropathy but can also be asymptomatic. Central nervous system manifestations are most frequent in Caucasians. Various clinical expression can be observed: neuro-endocrine symptoms, psychiatric symptoms, seizures, cognitive abnormalities, hydrocephalia, spinal cord impairment and various neurologic deficits. Brain and spinal cord MRI are the most sensitive tests to diagnose central nervous system sarcoidosis and guide therapeutical management. Cranial neuropathies prevale in Black patients. Although all cranial nerves can be concerned, seventh nerve palsy is the most common sign followed by optic neuropathy and involvement of the eighth and fifth nerves. Heerfordt's syndrome which associates uveitis, parotid gland enlargement, fever and cranial neuropathy, usually seventh nerve palsy, is highly suggestive of sarcoidosis. The diagnosis of neurosarcoidosis relies on the conjunction of: (i) confirmed sarcoidosis, (ii) neurologic involvement compatible with neurosarcoidosis and (iii) exclusion of an alternative neurologic disorder.
Clinically significant involvement of kidneys is extremely rare, cited in 0.7% of cases [9, 33]. Histology typically reveals granulomatous interstitial nephritis. Biology shows decreased creatinine clearance and low or absent proteinuria. Sarcoidosis can also produce urinary lithiasis and nephrocalcinosis while the relations between diverse forms of glomerulonephritis which are very uncommon and sarcoidoisis are very unclear.
Parotid enlargement is seen in 5–10% of cases. Sarcoidosis of the upper respiratory tract occurrs in 0.7 and 6 % and may assume various features in relation to the involvement of sinonasal mucosa, pharynx and larynx. Laryngeal sarcoidosis is potentially serious by provoking airway obstruction. Sinonasal sarcoidosis is well-recognised to be a chronic and recalcitrant form of the disease, which is associated with lupus pernio in half cases [34, 35]. Typically, patients complain of chronic crusting rhinitis but sinonasal involvement can occasionally lead to bone lysis and eventually disfiguiring saddle nose [35]. Articular involvement may be acute and transient or chronic and persistent [36]. Yet, whilst joint pains occur in 25–39% of patients with sarcoidosis, deforming arthritis is rare. Osseous involvement is associated with characteristic abnormalities on radiography [36]. Sarcoidosis usually affects small joints of the hands and feet, knees, ankles, elbows and wrists. Sympomatic muscle involvement is particularly unfrequent (1.4–2.3% cases). Gastrointestinal tract is involved in less than 1.0%. The stomach is the most commonly involved part of gastronintestinal tract, sometimes diagnosed incidentally [37]. Sarcoidosis of the small intestine and colon is much rarer and may mimic Crohn's disease. Pancreas and peritoneal localizations are exceptional. Splenic enlargement is observed in 5–10%, it is usually minimal and asymptomatic and causes rarely decrease in the count of platelets, red and white cells [37]. In the absence of splenomegaly, hematological alterations may be exceptionally due to a granulomatous infiltration of the bone marrow or to an autoimmune process, mainly hemolytic anemia or thrombopenia [37]. However, the most frequent abnormality is lymphopenia, which mechanism is a redistribution of blood T cells to sites of disease.
Biologic manifestations
Hypercalcemia is present in around 11% and hypercalciuria in around 36% of cases [33]. Serum angiotensin converting enzyme (SACE) is believed to reflect disease activity and dissemination but it is increased in about 60% of cases [24]. Serum protein electrophoresis shows polyclonal hypergammaglobulinemia in half cases. Hypogammaglobulinemia must prompt clinicians to seek alternative diagnosis to sarcoidosis, mainly variable common immunodeficiency and lymphoma. Routine blood tests are useful to evidence abnormal hepatic function and more rarely increased creatinine, and hematologic abnormalities, as discussed above.
Special situations
Sarcoidosis and pregnancy
Sarcoidosis does not influence pregnancy adversely. Whether or not the disease improves during pregnancy remains debated. On the other hand, it is clear that sarcoidosis may exacerbate again in the puerperium, which justifies a close surveillance within a period of 6 months after delivery. Pregancy should be avoided when treatments other than corticosteroids are necessary because of potential foetal toxicity or teratogenicity [37]. It is also contra-indicated in case of severe visceral involvement, particularly advanced respiratory insufficiency.
Sarcoidosis in children
Sarcoidosis is rare before the age of 15 and exceptional before 4. The disease of chidren resembles that of adults with respect to the distribution of organs involved. In old literature, sarcoidosis with an onset in children under the age of 4 has been reported to have an original presentation characterized by the combination of polyarthritis, uveitis and skin rash, and the rarity of intrathoracic involvement. It is likely that most of reported cases had actually Blau syndrome.
Association of sarcoidosis with other conditions
Co-existence of sarcoidosis with diverse autoimmune conditions, other granulomatosis and proliferations in the same individual is classical, even though still controversial. These include all connective tissue diseases but principally scleroderma and Sjogren's syndrome, as well as ankylosing spondilitis, primary biliary cirrhosis and auto-immune disorders of the thyroid [37]. Interestingly, an association with Crohn's disease, another granulomatous disease of unknown cause, has been reported [37]. Finally, association of lymphoproliferative and solid malignancies must be kept in mind and can raise difficult diagnosis problems.