Medicine – Granulomatous Lung Disease: Sarcoidosis

Sarcoidosis is a systemic granulomatous inflammatory disease that can involve almost any organ, although the lungs and intrathoracic lymph nodes are most commonly affected. Its pathological hallmark is the formation of non-caseating granulomas. The clinical course is highly variable: some patients remain completely asymptomatic and undergo spontaneous resolution, whereas others develop chronic progressive disease with irreversible organ damage.

1. Multisystem Disease

Sarcoidosis is a multisystem disorder, meaning that several organs may be affected simultaneously. Pulmonary involvement is particularly common, but disease can also occur in the skin, eyes, heart, liver, spleen, nervous system, bones, and joints.

The extent of organ involvement varies considerably between patients, making sarcoidosis a disease with a broad range of clinical presentations.

2. Cause

The precise cause of sarcoidosis remains unknown. It is thought to result from an exaggerated immune response to one or more unidentified environmental or infectious antigens in genetically susceptible individuals.

The immune response leads to accumulation of activated T lymphocytes and macrophages and ultimately to the formation of granulomas within affected tissues.

3. Age Distribution

Sarcoidosis commonly affects young and middle-aged adults, although it can occur at virtually any age.

Many patients develop the disease between approximately 20 and 40 years of age, with demographic patterns varying between populations.

4. Ethnic and Geographic Variation

The incidence and clinical severity of sarcoidosis vary considerably according to ethnicity and geographic region.

Older teaching commonly describes sarcoidosis as approximately three times more common in Black populations than White populations, particularly based on US data. More broadly, modern epidemiological studies confirm a substantially increased incidence in some populations of African ancestry, although the exact magnitude varies by location and population studied.

5. Non-Caseating Granulomas

The characteristic pathological lesion of sarcoidosis is the non-caseating granuloma. These granulomas consist predominantly of organised collections of epithelioid macrophages and multinucleated giant cells surrounded by lymphocytes.

Unlike the granulomas classically associated with tuberculosis, sarcoid granulomas usually lack central caseous necrosis.

However, finding a non-caseating granuloma is not by itself diagnostic of sarcoidosis. Other causes of granulomatous inflammation, particularly tuberculosis, fungal infection, occupational exposure, and certain drug reactions, must be excluded according to the clinical setting.

6. Genetic Associations

Sarcoidosis has a genetic component, with particular HLA alleles associated with susceptibility, clinical phenotype, and prognosis.

Older descriptions emphasised associations with HLA-A1, HLA-B8, and HLA-DR3. Modern genetic studies show that the relationship is more complex, with several HLA class II variants associated with different forms and outcomes of the disease.

Pulmonary Manifestations

7. Clinical Features

Pulmonary sarcoidosis has a highly variable presentation. Some patients have no respiratory symptoms and are diagnosed incidentally after an abnormal chest radiograph performed for another reason.

Other patients develop persistent dry cough, exertional shortness of breath, chest discomfort, fever, fatigue, and weight loss.

Respiratory Examination

Physical examination can be surprisingly normal despite significant radiological abnormalities.

Inspiratory crackles may occur when there is substantial interstitial lung involvement. Finger clubbing is uncommon in sarcoidosis; its presence should suggest advanced fibrotic disease or prompt consideration of an alternative diagnosis.

Bilateral Hilar Lymphadenopathy

Bilateral hilar lymphadenopathy (BHL) is one of the most characteristic radiological manifestations of sarcoidosis.

The combination of bilateral hilar lymphadenopathy and erythema nodosum, particularly in a young adult with compatible symptoms, is highly suggestive of sarcoidosis and may form part of the acute presentation known as Löfgren syndrome.

Pulmonary Fibrosis

Most patients do not progress to severe fibrosis, but chronic pulmonary sarcoidosis can eventually produce irreversible pulmonary fibrosis.

Fibrotic disease classically has an upper- and mid-zone predominance, unlike some other fibrotic interstitial lung diseases that predominantly affect the lung bases. Advanced disease can produce architectural distortion, traction bronchiectasis, respiratory impairment, and pulmonary hypertension.

Diagnosis

8. Establishing the Diagnosis

Diagnosis is based on a combination of a compatible clinical and radiological presentation, histological demonstration of non-necrotising granulomatous inflammation when required, and exclusion of alternative causes of granulomatous disease.

No single blood test is sufficiently specific to establish the diagnosis.

Tissue Biopsy

When histological confirmation is required, tissue should ideally be obtained from the safest and most accessible affected site.

Bronchoscopy may be used to obtain transbronchial lung biopsies. In patients with enlarged hilar or mediastinal lymph nodes, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is also widely used.

Biopsy typically demonstrates non-caseating granulomas, but infectious causes such as tuberculosis must be excluded before attributing the findings to sarcoidosis.

Hypercalcaemia

Sarcoidosis may cause hypercalcaemia and/or hypercalciuria. Activated macrophages within granulomas can increase production of active vitamin D, resulting in increased intestinal calcium absorption.

Persistent abnormalities of calcium metabolism may contribute to renal calculi and renal impairment.

Serum ACE

Serum angiotensin-converting enzyme (ACE) levels may be elevated because ACE can be produced by cells within sarcoid granulomas.

However, serum ACE has limited sensitivity and specificity and cannot reliably confirm or exclude sarcoidosis. It should therefore be interpreted only as a supportive finding in the appropriate clinical context.

Chest Radiograph Staging

Stage 0 – Normal Chest Radiograph

In Stage 0, the chest radiograph is normal despite the possibility of sarcoidosis involving extrapulmonary organs.

Stage I – Bilateral Hilar Lymphadenopathy

Stage I consists of bilateral hilar lymphadenopathy without pulmonary infiltrates. This pattern is commonly associated with a favourable prognosis and spontaneous resolution.

Stage II – BHL with Pulmonary Infiltrates

Stage II consists of bilateral hilar lymphadenopathy together with pulmonary parenchymal infiltrates.

Both the intrathoracic lymph nodes and lung tissue are therefore visibly involved.

Stage III – Pulmonary Infiltrates Without BHL

Stage III is characterised by pulmonary infiltrates without bilateral hilar lymphadenopathy.

This represents more prominent parenchymal pulmonary involvement.

Stage IV – Pulmonary Fibrosis

An important addition to the older classification in your notes is Stage IV, which represents established pulmonary fibrosis.

There may be upper-lobe volume loss, architectural distortion, fibrotic bands, traction bronchiectasis, and other features of chronic irreversible lung disease.

Extrapulmonary Manifestations

9. Liver

Hepatic involvement is relatively common and is frequently asymptomatic. Granulomas may be found within the liver even when there is little or no clinically apparent hepatic disease.

Some patients develop abnormal liver function tests, hepatomegaly, or, rarely, clinically significant chronic liver disease.

10. Cardiac Sarcoidosis

Cardiac involvement is particularly important because it can produce serious or potentially life-threatening complications.

Granulomatous inflammation and subsequent fibrosis can interfere with the cardiac conduction system and myocardium, producing atrioventricular block, ventricular arrhythmias, cardiomyopathy, heart failure, or sudden cardiac death.

The frequency of clinically apparent cardiac sarcoidosis is considerably lower than some older quoted figures of 30–70%, although occult cardiac involvement may be detected more frequently at imaging or autopsy.

11. Skin

Approximately one-quarter of patients may develop cutaneous manifestations.

Erythema nodosum produces painful, tender red nodules, typically over the shins, and is particularly associated with acute sarcoidosis.

Other manifestations include papules, plaques, subcutaneous nodules, and lupus pernio. Lupus pernio consists of chronic violaceous lesions, particularly affecting the nose, cheeks, ears, and other facial areas, and tends to be associated with more chronic disease.

12. Eyes

Ocular involvement most commonly presents as uveitis, particularly anterior uveitis.

Patients may develop eye pain, redness, photophobia, and visual disturbance. Because untreated ocular inflammation can threaten vision, ophthalmological assessment is important when eye involvement is suspected.

13. Splenic Involvement

The spleen may be infiltrated by granulomas, resulting in splenomegaly.

Significant splenic involvement can occasionally contribute to cytopenias through hypersplenism.

14. Neurological Sarcoidosis

Neurosarcoidosis occurs in a minority of patients but can affect almost any part of the nervous system.

Manifestations include cranial nerve palsies, meningitis, hydrocephalus, hypothalamic or pituitary disease, peripheral neuropathy, spinal cord involvement, and mass-like intracranial lesions.

Cranial neuropathy, particularly facial nerve palsy, is a well-recognised presentation.

15. Bone and Joint Disease

Sarcoidosis may involve the bones and joints. Chronic osseous sarcoidosis can produce cystic or lytic lesions, particularly in the small bones of the hands and feet.

Musculoskeletal disease may also present with arthralgia or inflammatory arthritis, with ankle involvement being particularly characteristic of acute sarcoidosis.

Löfgren Syndrome

Löfgren syndrome is an acute and characteristic presentation of sarcoidosis. It classically consists of the triad of:

Bilateral hilar lymphadenopathy + erythema nodosum + acute arthritis or periarthritis, particularly affecting the ankles.

It usually has a favourable prognosis, and spontaneous resolution is common.

Treatment

16. Observation and Symptomatic Treatment

Not every patient with sarcoidosis requires specific treatment. Patients with mild or asymptomatic disease and preserved organ function may be monitored because spontaneous remission is common.

Symptomatic treatment can be provided when necessary, together with regular assessment for progression or important organ involvement.

17. Corticosteroids

Systemic corticosteroids are a mainstay of treatment when sarcoidosis causes significant symptoms, progressive pulmonary disease, or clinically important extrapulmonary organ involvement.

Treatment is particularly important when there is potentially serious involvement of organs such as the heart, nervous system, or eyes, although management depends on the specific manifestation.

18. Immunosuppressive Therapy

When corticosteroids are ineffective, cause unacceptable adverse effects, or prolonged steroid-sparing treatment is required, additional immunosuppressive therapy may be used.

Methotrexate is a commonly used steroid-sparing agent. Other therapies may include azathioprine, mycophenolate, or selected biologic agents such as anti-TNF therapy in difficult refractory disease.

Key Clinical Pattern

Think of sarcoidosis in a young or middle-aged adult presenting with bilateral hilar lymphadenopathy, dry cough or dyspnoea, erythema nodosum, uveitis, or ankle arthritis.

The pathological hallmark is a non-caseating granuloma, but other granulomatous diseases—especially tuberculosis and fungal infection—must be excluded.

A particularly memorable presentation is Löfgren syndrome: bilateral hilar lymphadenopathy + erythema nodosum + acute ankle arthritis/periarthritis. Pulmonary disease may resolve spontaneously, but a minority of patients develop chronic disease and irreversible pulmonary fibrosis.