Pulmonary Sarcoidosis

A multisystem disorder of unknown cause resulting in non-caseating granulomas in one or more organs and tissues (as opposed to the caseating granulomas of TB). The lungs and lymphatic system are most often affected, but any organ can be involved. Pulmonary disease occurs in over 90% of adults with sarcoidosis, commonly with bilateral hilar lymphadenopathy.

Most commonly affects people aged 20 to 40 years. Incidence is roughly 17 to 35 per 100,000, with a male-to-female ratio of 2:1.

Illness script

Cough, fever, malaise, erythema nodosum, anterior uveitis, with bilateral hilar lymphadenopathy on CXR. Most cases are probably asymptomatic and go undetected.

Symptoms depend on the site and degree of involvement and vary over time, ranging from spontaneous remission to chronic indolent illness — so reassess regularly for new symptoms and new organ involvement.

Other manifestations to ask about: painful red skin lumps, blurred vision from uveitis, hoarseness, palpable nodes in the axilla and neck, painful swollen joints, hearing loss, seizures. Ocular involvement occurs in around half of patients, uveitis being the commonest form.

Lofgren syndrome is an acute, self-limited form with the triad of lymphadenopathy, erythema nodosum and arthritis.

Cardiac involvement is the most common cause of death in sarcoidosis, followed by respiratory failure. Conduction block and sudden cardiac death are reported.

Diagnosis (ATS/ERS/JRS/ALAT 2020 guideline)

Diagnosis requires all three of:

1. A compatible clinical presentation
2. Non-necrotising granulomatous inflammation on tissue biopsy (bronchial biopsy, or skin biopsy if erythema nodosum is present)
3. Exclusion of alternative causes of granulomatous disease

Sarcoidosis is most often suspected when hilar adenopathy, with or without lung infiltrates, is incidentally found on chest radiography — bilateral hilar adenopathy is the commonest abnormality, and CXR should be the first test.

Histology shows non-caseating granulomas with aggregates of epithelioid histiocytes, giant cells and mature macrophages. The key feature is the absence of mycobacteria and fungi within those granulomas.

Radiographic staging

• Stage I — bilateral hilar adenopathy alone
• Stage II — bilateral hilar adenopathy with reticular opacities
• Stage III — reticular opacities with shrinking hilar nodes
• Stage IV — fibrosis

Stage roughly predicts the likelihood of spontaneous remission, but it can mislead about severity — extrapulmonary disease, particularly cardiac, is not captured by it.

Baseline screening (even without organ-specific symptoms)

• Baseline serum calcium testing is strongly recommended in all patients with sarcoidosis who do not have symptoms or signs of hypercalcaemia.
• Baseline ocular examination, serum creatinine, and serum alkaline phosphatase are conditionally recommended for all patients, even in the absence of relevant symptoms.
• Serum ALP (conditional — hepatic sarcoidosis screening); a raised ALP suggests diffuse granulomatous hepatic involvement
• Baseline ECG is conditionally recommended for all patients with extracardiac sarcoidosis and no cardiac symptoms; routine echo or 24-hour Holter is not standard screening.
• For suspected cardiac sarcoidosis, cardiac MRI is preferred over PET or transthoracic echo for both diagnostic and prognostic information.

Other supporting evidence: elevated serum ACE (non-specific), restrictive spirometry pattern. ESR and CRP are commonly raised but non-specific. A DLCO under 60% predicted with walk-test saturation under 90% should prompt evaluation for pulmonary hypertension.

Differential diagnosis

Tuberculosis and other mycobacterial infection, fungal infection, hypersensitivity pneumonitis, berylliosis, lymphoma, and granulomatosis with polyangiitis.

Treatment

Pulmonary sarcoidosis is often asymptomatic and non-progressive and requires no treatment, because most patients undergo spontaneous remission. No treatment is required for hilar lymphadenopathy alone. Monitor symptoms, chest radiography and lung function at intervals in asymptomatic patients.

Corticosteroid treatment is indicated if:

• No spontaneous improvement in 3-6 months
• Symptomatic pulmonary lesions
• Eye, CNS or other extrapulmonary system involvement
• Hypercalcaemia or hypercalciuria
• Erythema nodosum with arthralgia
• Persistent cough

Dosing: prednisolone starting at 20 mg once a day, with follow-up dosing of 5-10 mg once a day to once every other day. This is a lower, more standardised starting dose than the previous weight-based 0.5 mg/kg (max 50 mg) regimen. Two studies found no additional benefit for treating pulmonary disease with more than 20 mg prednisone a day.

For untreated patients with major involvement believed to be at higher risk of future mortality or permanent disability, ERS makes a strong recommendation to introduce glucocorticoid treatment to improve or preserve FVC and quality of life. Continue for 1-3 months before clinical reassessment. Around half of patients started on glucocorticoids are still on treatment two years later, so re-evaluate the need to continue.

Escalation, if glucocorticoids fail or aren’t tolerated:

• Methotrexate 10-15 mg once a week, suggested as the addition to improve or preserve FVC and quality of life.
• Infliximab 3-5 mg/kg, suggested for patients who have also failed a second-line agent.

The Cochrane review of 13 randomised trials in 1066 participants found oral steroids improved the chest X-ray and a global score of CXR, symptoms and spirometry over 3-24 months, but there is little evidence of improvement in lung function, and limited data beyond two years on whether steroids modify long-term disease progression. It concluded oral steroids may be of benefit for patients with stage 2 and 3 disease with moderate to severe or progressive symptoms or CXR changes.

Steroid-sparing agents are used where corticosteroids are not tolerated; biologics for non-responders; lung transplant for end-stage disease.

Counsel patients about the risk of hypercalcaemia and to avoid unnecessary vitamin D or calcium supplementation unless directed.