Sarcoidosis – a multi-system disorder, is characterized by non-caseating inflammation at the affected sites. It usually affects the lungs and intrathoracic lymph nodes (LN).

It is triggered by exposure to microbial agents in people with a genetic susceptibility to the disease. Sarcoidosis is commonly diagnosed during adulthood, and the lifetime risk is higher in females. The prevalence is 10-40 cases per 1,00,00 population, and the mortality rate is 1-5%. The majority of the associated deaths occur due to advanced pulmonary disease. The Black race is more susceptible than the Whites. 

Etiology: The exact cause remains uncertain. Sarcoidosis can be infective and non-infective. A smoking-negative association has been described. Genetic factors also play a crucial role.

Pathology: The hallmark feature is non-caseating epithelioid granulomas. The dominant cell in the core is an epithelioid cell-modified mononuclear phagocyte. CD4+ and CD8+ T cells and B lymphocytes can be seen in the periphery. Characteristic Schaumann bodies and Hamazaki-Wesenberg bodies are present.

Clinical Classification: Asymptomatic: may detect bilateral pulmonary infiltrates with hilar adenopathy.

• Acute sarcoidosis – with or without erythema nodosum: is characterized by bilateral hilar adenopathy, fever, polyarthritis, and uveitis – termed Lofgren Syndrome; excellent prognoses.
• Sarcoidosis with signs and symptoms of the pulmonary disease for <2 yrs: nonproductive cough along with progressive dyspnea on exertion; chest pain; hemoptysis; sometimes, upper lobe crackles can be appreciated.
• Chronic pulmonary sarcoidosis of >2 yrs 
• Dominant extrapulmonary sarcoidosis
• Fibrocystic sarcoidosis

Investigations: Chest Imaging (CXR): in Pulmonary Sarcoidosis – mediastinal lymphadenopathy, commonly bilateral hilar lymphadenopathy, parenchymal infiltrates at middle and upper lung fields. It may resemble tuberculosis. 

Garland Triad – right paratracheal node enlargement, right hilar node enlargement, and left hilar node enlargement.

Staging – is based on CXR and differentiates according to lymphadenopathy, parenchymal changes, and fibrosis.

• CT Scan: Mid-to-upper lung predominance; central infiltrates, following broncho-vascular bundles. Ground-glass or honey-comb pattern. Multiple discrete enlarged LN. Other signs include – Galaxy sign, Reverse Halo, and Sarcoid Cluster.
• Gallium 67 scanning: Characteristic lambda sign – bilateral hilar and right paratracheal LN enlargement.
• Pulmonary Function Tests: Classical obstruction; DLCO may be decreased; restrictive disease; pulmonary hypertension.
• Bronchoscopy: Endobronchial appearance; elevated BAL lymphocyte count; CD4:CD8 ratio>4.
• Biopsy: the yield from Endobronchial biopsy (EBB) is 40-60%; the yield from Transbronchial biopsy (tbbx) is 40-90%.
• Serum Markers: ACE enzyme; Chitotriosidase; soluble IL-2 receptor.
• FDG-PET – cardiac sarcoidosis; active pulmonary lesion; advanced pulmonary sarcoidosis.

Types of Sarcoidosis:

• Ocular Sarcoidosis – Uveitis is the most common.
• Cardiac Sarcoidosis – is associated with arrhythmias, heart block, and sudden death.
• Neurosarcoidosis – Cranial meningitis, aseptic encephalitis, hypothalamic-pituitary dysfunction, or peripheral neuropathies.
• Cutaneous Sarcoidosis – SC nodules, lupus pernio, erythema nodosum.
• Hepatic Sarcoidosis – Hepatic inflammation with fever; progressive cirrhosis.
• Hematologic Sarcoidosis – Splenomegaly; peripheral lymphopenia; bone marrow granulomas.

Manifestations

• Joint and Musculoskeletal – arthralgias; polyarthritis; myopathies.
• Exocrine Gland – enlargement; may cause facial palsy; Heerfordt Syndrome; Panda sign – bilateral involvement of parotic and lacrimal glands.
• Endocrine and Renal – hypercalciuria, hypercalcemia, kidney stones, renal failure.
• Gastrointestinal – direct esophageal involvement, gastric sarcoidosis, genitourinary masses. 
• Psychosocial – depression, fatigue, fibromyalgia; para-sarcoidosis syndrome.

Diagnosis

The diagnosis is based on:

• Compatible clinical presentation
• Necrotizing granulomatous inflammation in tissue samples
• Exclusion of alternative causes of granulomatous disease

Clinical Symptoms

• Lupus pernio
• Uveitis
• Optic neuritis
• Erythema nodosum
• Heerfordt Syndrome
• Lofgren Syndrome

Differential Diagnosis

• Tuberculosis and atypical mycobacterial infections
• Fungal infections
• Blood-lymphocyte proliferation

ATS 2020 recommendations

• Lymph Node Sampling is not required in cases with high clinical suspicion.
• In asymptomatic, bilateral hilar lymphadenopathy – there is no recommendation for or against LN sampling.
• EBUS/Mediastinoscopy – if tissue sampling is necessary, EBUS-guided LN sampling is preferred. 

Screening for Extrapulmonary Disease – ATS 2020 Recommendations 

• Baseline eye examination.
• Baseline serum-creatinine testing.
• Baseline serum-alkaline phosphatase testing.
• No recommendation for or against serum-transaminase testing.

ATS 2020 Recommendations

• Asymptomatic patients – baseline serum-calcium testing.
• Vitamin D supplementation recommended – measure both 25- and 1,25-OH Vitamin D prior.
• Hematological abnormalities – baseline CBC test.
• Extracardiac Sarcoidosis; asymptomatic – ECG; cardiac MRI, rather than PET or TTE.
• Sarcoidosis with Pulmonary hypertension (PH) – initial testing with TTE.
• If TTE-indicated PH – right heart catheterization is required.

Management

• In cases with intrathoracic lymphadenopathy or asymptomatic sarcoidosis – no treatment is required.
• Oral Corticosteroids – first-line therapy in progressive disease; Prednisolone 20-40 mg per day or equivalent.
• Bisphosphonates – to reduce steroid-induced osteoporosis.
• Inhaled Corticosteroids – for cough and bronchial hyperactivity.
• Steroid-sparing immunosuppressive or anti-inflammatory treatments – if corticosteroids fail to render adequate benefits; Methotrexate or Azathioprine.
• Lung/Heart transplantation – end-stage organ damage.
• Investigational agents – can be used in the third line.

Prognoses and Dosage

Pulmonary sarcoidosis typically shows treatment response within 3-4 weeks of therapy commencement. The corticosteroid dose is tapered after gauging the treatment response – stepwise thereafter. At least six months’ treatment is warranted in sarcoidosis cases with recent onset (<5 years). 

Chances of relapse range from 14-17% in acute disease and 75% in chronic cases. In case of a relapse – repeat therapy with previously determined effective doses. 

Alternative Agents

Non-Immunosuppressive Drugs:

• Hydroxy-chloroquine
• Tetracycline, Minocycline, Doxycycline
• Pentoxyfilline
• Metatonin
• Thalidomide

Immunosuppressive Drugs:

• Methotrexate
• Azathioprine
• MMP, Leflunomide, Cycliophosphamide
• Anti-TNF, Infliximab