What is Pulmonary Sarcoidosis
Pulmonary sarcoidosis is a chronic, multisystem inflammatory disease of unknown cause characterized by non-caseating (non-necrotic) granulomas that predominantly affects the lungs and intrathoracic lymph nodes, occurring in over 90% of all sarcoidosis cases. 1, 2
Definition and Core Pathophysiology
Sarcoidosis is fundamentally a granulomatous disease where well-formed granulomas develop with a central core of macrophage aggregates and multinucleated giant cells, surrounded by loosely organized lymphocytes 2
The disease involves abnormal T cell-mediated immune responses with accumulation of CD4+ T cells and release of pro-inflammatory cytokines (IL-2, TNF), leading to non-caseating granuloma formation 2
The cause remains unknown, though the disease develops in genetically predisposed individuals exposed to an unidentified antigen, possibly including self-antigens suggesting autoimmune involvement 3
These granulomas are typically non-necrotic, distinguishing them from infectious granulomas like tuberculosis, though variants can present with mixed necrotic and non-necrotic patterns 2
Epidemiology and Risk Factors
Prevalence varies widely from less than 10 to over 80 per 100,000 population depending on age, gender, ethnicity, and geographic location 1
African Americans and northern Europeans (particularly Scandinavians) have higher incidence rates, with age-adjusted incidence of approximately 11 cases per 100,000 in Caucasians 2, 4
Women experience higher morbidity and mortality, with African American women having 2.4 times higher mortality compared to matched cohorts without sarcoidosis 2
The disease most commonly affects young and middle-aged adults of all races and both sexes 1
Clinical Presentation
More than 50% of patients are asymptomatic when diagnosed by radiographic screening, making incidental detection common 1
Among symptomatic patients, cough (with or without scant mucoid sputum) occurs in 40-80%, along with shortness of breath, chest pain, and pronounced fatigue 1, 3
Bilateral hilar lymphadenopathy is the hallmark radiographic finding, often accompanied by perilymphatic nodules on chest CT 1, 2
Three pathognomonic syndromes are diagnostic without requiring biopsy: Löfgren's syndrome (bilateral hilar adenopathy, erythema nodosum, arthritis), lupus pernio (chronic violaceous skin lesions), and Heerfordt's syndrome (uveitis, parotid enlargement, fever, facial nerve palsy) 1, 5
Diagnostic Approach
Diagnosis requires three essential criteria: (1) compatible clinical and radiologic presentation, (2) histologic demonstration of non-caseating granulomas, and (3) exclusion of alternative causes like infections (especially tuberculosis) or malignancy 1, 4
Tissue sampling is typically necessary via endobronchial ultrasound (EBUS), fine needle aspiration, or transbronchial lung biopsy to obtain histologic confirmation 1
EBUS-guided lymph node sampling has 87% diagnostic yield, with 98% confirming sarcoidosis and 2% finding alternative diagnoses including lymphoma and tuberculosis 1
High-resolution chest CT is the imaging modality of choice, more reliable than chest radiographs for identifying characteristic changes 1
Baseline testing should include: serum ACE level, serum calcium, alkaline phosphatase, complete blood count, pulmonary function tests, and electrocardiogram to assess for cardiac involvement 2, 6
Bronchoalveolar lavage showing lymphocytosis or elevated CD4:CD8 ratio supports the diagnosis 2
Important Diagnostic Caveat
In patients with pathognomonic syndromes (Löfgren's, lupus pernio, Heerfordt's), lymph node sampling is NOT recommended 1
For asymptomatic bilateral hilar lymphadenopathy, no firm recommendation exists for or against sampling, but close clinical follow-up is essential if biopsy is deferred 1
Before attributing cough solely to sarcoidosis, exclude more common causes like upper airway cough syndrome, asthma, and GERD, as these may coexist 1
Disease Staging and Prognosis
Scadding radiographic stages correlate with clinical outcomes and guide prognosis 7:
- Stage I (bilateral hilar lymphadenopathy alone): 30-80% radiographic remission
- Stage II (lymphadenopathy plus parenchymal infiltrates): 30-80% remission
- Stage III (parenchymal infiltrates without lymphadenopathy): only 10-40% resolution
- Stage IV (pulmonary fibrosis): no chance of resolution
Up to 40% of patients progress to Stage IV disease with lung parenchymal fibrosis, bronchiectasis, hilar retraction, and fibrocystic disease 7
Overall mortality is approximately 7% at 5 years, with more than 60% of sarcoidosis deaths due to advanced cardiopulmonary disease (except in Japan where >70% are from cardiac sarcoidosis) 7, 8
Stage IV patients with precapillary pulmonary hypertension (occurring in up to 70% of advanced cases) have the highest mortality risk at >40% at 5 years 7, 8
Treatment Indications and Strategy
Many patients with asymptomatic bilateral hilar lymphadenopathy have self-limited disease and do NOT require treatment, as spontaneous remission rates range from 10-82% 2, 8
When to Treat
Treatment should be initiated for: 1
- Progressive radiographic changes
- Persistent or troublesome pulmonary symptoms (cough, dyspnea, chest pain)
- Lung function deterioration (TLC decline ≥10%, FVC decline ≥15%, DLCO decline ≥20%)
- Concomitant involvement of critical extrapulmonary organs (cardiac, neurologic, ocular, renal)
- Sarcoid-related hypercalcemia
First-Line Treatment
Oral corticosteroids are the mainstay of therapy for symptomatic patients with parenchymal infiltrates and abnormal pulmonary function tests 9, 7, 8
Prednisone 20-40 mg daily for 2 weeks to 2 months is the typical starting dose, which can be tapered over 6-18 months if symptoms, spirometry, and radiographs improve 7, 8
Prolonged prednisone may be required to stabilize disease, but doses should be minimized due to significant side effects 1
Second and Third-Line Treatments
Immunosuppressive agents (methotrexate, azathioprine) are second-line options for patients requiring prolonged prednisone ≥10 mg/day or those with glucocorticoid adverse effects 7, 8
Anti-TNF medications (infliximab, adalimumab) are third-line treatments for refractory cases, used alone or as glucocorticoid-sparing agents 6, 7
Appropriate microbial prophylaxis for Pneumocystis jiroveci and herpes zoster should accompany immunosuppressive therapy 8
Special Populations
Patients with precapillary pulmonary hypertension should receive targeted pulmonary arterial hypertension medications (phosphodiesterase inhibitors, prostacyclin analogues) in addition to immunosuppression 7, 8
No effective treatments exist for advanced fibrocystic pulmonary disease, and end-stage disease may require lung transplantation 8, 4
Key Clinical Pitfalls
Sarcoidosis can mimic malignant disease progression, so both clinicians and radiologists must maintain awareness of this possibility 1
Relapse rates range from 13-75% depending on disease stage, number of organs involved, socioeconomic status, and geography, necessitating long-term follow-up 7
Extrapulmonary manifestations require specific evaluation: eye examination and baseline ECG should be performed once diagnosis is established to investigate cardiac and ocular involvement 1
Hematologic alterations are common, including anemia of chronic disease, leukocytosis, and reactive thrombocytosis as part of the systemic inflammatory response 2