Sarcoidosis — Pulmonary

• Antigen processing and Th1/Th17 immune activation: Environmental or infectious antigens (proposed candidates include beryllium, organic dust, mycobacterial proteins, and infectious agents such as Propionibacterium acnes) are processed by lung-resident dendritic cells and alveolar macrophages and presented via MHC class II molecules to CD4+ T cells. This drives aberrant Th1 and Th17 differentiation with excessive IL-2, IFN-γ, IL-6, and IL-17 production. Patients with sarcoidosis demonstrate a paradoxical immune phenotype: despite Th1/Th17 activation systemically, there is concurrent reduced delayed-type hypersensitivity (anergy) at the tuberculin skin test level, suggesting complex T-regulatory cell dysfunction and IL-2 sequestration at sites of disease.

• Macrophage-mediated granuloma formation and epithelioid transformation: Activated macrophages fuse to form multinucleated giant cells and epithelioid cells, creating noncaseating granulomas—the pathologic hallmark. Unlike tuberculosis granulomas, sarcoid granulomas lack central necrosis (caseation). Macrophages produce abundant TNF-α, which is critical for both granuloma maintenance and systemic manifestations (fever, fatigue, hypercalcemia). Monocytes differentiate into ACE (angiotensin-converting enzyme)-producing cells, leading to elevated serum and urine ACE levels and enhanced local angiotensin II production, which promotes fibroblast proliferation and collagen deposition. Granulomas in pulmonary sarcoidosis predominantly affect the upper and middle lung zones and follow lymphatic pathways, appearing along bronchovascular bundles and hilar mediastinal stations.

• Fibrotic progression and pulmonary remodeling: In a subset of patients (10-20% of those with pulmonary involvement), granulomatous inflammation progresses to pulmonary fibrosis through macrophage-derived TGF-β and fibroblast growth factor signaling. Repeated granuloma formation, resolution, and healing lead to progressive interstitial fibrosis predominantly in upper lobes, distinguishing sarcoidosis from idiopathic pulmonary fibrosis (IPF), which favors lower lobes. Advanced fibrosis results in restrictive physiology, pulmonary hypertension, and eventual cor pulmonale. Additionally, some patients develop bronchial distortion and airway involvement, causing obstructive pattern on spirometry.

• Dysregulated calcium and phosphate metabolism: TNF-α-producing macrophages in granulomas activate the 1α-hydroxylase pathway in macrophage lysosomes, converting 25-hydroxyvitamin D to calcitriol (active 1,25-dihydroxyvitamin D) independent of parathyroid hormone regulation. This leads to hypercalcemia (in 2-10% of patients) and hypercalciuria (in 20-50%), which can cause nephrolithiasis, nephrogenic diabetes insipidus, and progressive renal dysfunction.

• Genetic susceptibility factors: HLA associations (HLA-DRB1 and HLA-DQB1 alleles) confer increased disease susceptibility, and recent GWAS studies have identified associations with BTNL2 (butyrophilin-like 2), FAP (fibroblast activation protein), and other immune regulation genes. These findings suggest that disease develops in genetically predisposed individuals upon environmental exposure.

• Environmental and occupational exposures: Proposed environmental triggers include organic dusts, metals, and microbial antigens. Beryllium exposure historically was an important occupational hazard causing chronic beryllium disease (a beryllium-sensitized granulomatous disease distinctly different from sarcoidosis but clinically mimicking it); beryllium lymphocyte proliferation tests (BeLPT) help differentiate. Hypersensitivity pneumonitis from mold, bird antigens, or other organic dusts must be distinguished from sarcoidosis on clinical and histologic grounds (hypersensitivity pneumonitis features caseating granulomas less commonly and has acute symptoms with antigen re-exposure). Metallic dusts (aluminum, zirconium) have been studied but lack definitive causal links.

• Infectious agents and molecular mimicry: Mycobacterial antigens (particularly from Mycobacterium tuberculosis and M. avium complex) and bacterial lipopolysaccharides have been detected in sarcoid granulomas in some studies, suggesting that cross-reactive immune responses to environmental microbes may trigger disease in susceptible hosts through molecular mimicry. Propionibacterium acnes has been cultured from sarcoid granulomas in some cohorts. Viral infections (particularly EBV and HHV-8) have been epidemiologically associated, though causality remains unclear. These observations support an antigen-driven disease model in which chronic antigen presentation drives perpetual Th1/Th17 activation.

• Genetic predisposition: African Americans and Northern Europeans have higher prevalence and more severe disease, and familial clustering occurs in 5-10% of cases (suggesting autosomal inheritance with incomplete penetrance). HLA class II alleles (DRB1*0301, DQB1*0201) are enriched in sarcoidosis patients. BTNL2 polymorphisms reduce T-regulatory cell function and increase disease risk. FAP variants affect T-cell exhaustion pathways. These genetic factors likely determine whether environmental antigen exposure results in clinical sarcoidosis.

• Age and sex: Younger age (20-40 years) is a risk factor, though disease can present in childhood or the elderly. Women have slightly higher incidence but men have more severe and progressive disease, particularly regarding pulmonary fibrosis.

• Dyspnea: Progressive dyspnea on exertion is the most common symptom, resulting from several mechanisms: restrictive physiology (due to interstitial fibrosis and granulomatous inflammation reducing lung compliance), small airways disease (granulomas causing bronchial narrowing), and pulmonary hypertension (from hypoxemia, fibrosis, or direct pulmonary vascular involvement). Dyspnea worsens insidiously over months to years in progressive cases, though some patients remain stable. Acute dyspnea may occur with acute alveolitis or spontaneous pneumothorax (rare complication).

• Dry cough: A persistent, nonproductive cough affects 20-40% of symptomatic patients, driven by granulomatous inflammation of the tracheobronchial tree, airway distortion, and airway hyperresponsiveness. Cough may be accompanied by bronchial hyperreactivity (positive methacholine challenge in 20-40%), mimicking asthma.

• Constitutional symptoms: Fever, fatigue, and malaise occur in 20-30% of patients, mediated by TNF-α and other inflammatory cytokines produced by granulomas. Night sweats may be prominent. Weight loss occurs in some patients with systemic disease. These systemic symptoms may overshadow pulmonary symptoms in presentation.

• Chest pain and discomfort: Pleuritic chest pain occurs in 5-10% due to pleural involvement or inflammation around granulomas, and can be confused with cardiac ischemia or musculoskeletal pain.

• Acute presentations—Löfgren syndrome: Löfgren syndrome is an acute, self-limited form of sarcoidosis occurring predominantly in young women (female predominance 3:1) and characterized by the classic triad of (1) erythema nodosum (painful nodules on shins and extensor surfaces), (2) bilateral hilar lymphadenopathy, and (3) polyarthritis/polyarthralgia (typically affecting ankles, knees, wrists). Löfgren syndrome has excellent prognosis with >90% spontaneous remission within 2 years without treatment. Heerfordt syndrome (acute sarcoidosis with parotid gland enlargement, fever, and anterior uveitis) is another acute presentation with good prognosis. Recognition of these syndromes is important because they warrant minimal intervention and have favorable natural history.

• Heerfordt syndrome variant: Presents with parotitis, fever, anterior uveitis, and facial nerve palsy (parotitis may cause asymptomatic salivary gland enlargement or symptomatic swelling). This acute variant also typically resolves spontaneously.

• Physical examination findings: Rales (crackles) may be heard on lung auscultation, typically late inspiratory crackles in lower lobes (mimicking IPF) if fibrosis is present; however, many patients have clear lungs. Wheezing may be heard if airways are significantly involved. Lymph node enlargement (supraclavicular, cervical) occurs with systemic disease. Erythema nodosum (tender, nodular lesions on anterior tibiae) is the most common skin manifestation, seen in 5-25% depending on population. Hepatomegaly and splenomegaly occur in 5-10% and indicate systemic involvement. Ocular findings (uveitis is present in 20-25% of sarcoidosis patients overall) may include anterior chamber inflammation, keratic precipitates, and posterior synechiae. Cardiac findings (in ~5% with clinically apparent cardiac involvement, though autopsy suggests 25%) include arrhythmias, heart block, or signs of heart failure.

• Important clinical variants: Chronic progressive pulmonary sarcoidosis (50-60% of symptomatic patients) shows gradual worsening with fibrosis and functional decline. Asymptomatic radiographic sarcoidosis (25-30%) is discovered incidentally; many require no treatment. Some patients (10%) progress to end-stage pulmonary fibrosis with severe restriction and pulmonary hypertension, occasionally requiring lung transplantation.

• Diagnostic criteria and diagnostic pathway: The diagnosis of sarcoidosis is established when (1) compatible clinical presentation and radiographic findings coexist AND (2) histologic evidence of noncaseating granulomas is present (ideally from affected organ) AND (3) alternative diagnoses are reasonably excluded. Löfgren syndrome (bilateral hilar lymphadenopathy + erythema nodosum ± arthritis) can be diagnosed clinically without biopsy in the appropriate clinical context with high specificity. Diagnosis requires exclusion of tuberculosis, fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis), berylliosis, hypersensitivity pneumonitis, and malignancy (lymphoma).

• Chest imaging—High-Resolution CT (HRCT) and plain radiographs: HRCT chest is the gold standard imaging modality and reveals several characteristic patterns: (1) Bilateral hilar and mediastinal lymphadenopathy (>1 cm) affecting stations 2L, 2R, 4L, 4R, and 7 (paratracheal and subcarinal); (2) Parenchymal infiltrates in upper and middle zones (characteristic for sarcoidosis vs. lower-lobe predominance in IPF); (3) Nodular pattern (perilymphatic distribution along bronchovascular bundles and subpleural regions); (4) Ground-glass opacities; (5) Irregular or reticular opacities in advanced stages; (6) Traction bronchiectasis in fibrotic disease. Löfgren staging (Scadding) categorizes chest radiograph findings: Stage 0 (normal), Stage 1 (bilateral hilar lymphadenopathy only), Stage 2 (bilateral hilar lymphadenopathy + parenchymal infiltrates), Stage 3 (parenchymal infiltrates without lymphadenopathy), and Stage 4 (pulmonary fibrosis with volume loss). Stage 1 disease has best prognosis (70-90% spontaneous remission), while Stage 4 indicates advanced fibrosis with poor prognosis.

• Pulmonary function tests (PFTs): Spirometry typically shows restrictive pattern (reduced FVC, normal or elevated FEV1/FVC ratio) in advanced disease; some patients may show obstructive or mixed pattern if airways are involved. DLCO is often disproportionately reduced relative to FVC, reflecting alveolitis and granulomatous inflammation affecting gas exchange. Serial PFTs are essential for monitoring disease progression and treatment response. FVC decline >10% or DLCO decline >15% in 1 year suggests active disease progression. 6-minute walk test assesses functional limitation and oxygen desaturation with exercise.

• Laboratory findings—Serum ACE and calcium: Serum ACE (angiotensin-converting enzyme) is elevated in 40-60% of sarcoidosis patients, produced by epithelioid macrophages within granulomas; normal range is typically 8-52 U/L (varies by lab), and sarcoidosis typically shows levels >52 U/L. ACE elevation supports diagnosis but lacks sensitivity and specificity (also elevated in tuberculosis, fungal infections, and hypersensitivity pneumonitis). Serum calcium is elevated in 2-10% of patients (normal <10.5 mg/dL); hypercalciuria occurs in 20-50% (24-hour urine calcium >300 mg or spot urine calcium:creatinine ratio >0.3). Hypercalcemia/hypercalciuria reflects abnormal vitamin D metabolism by macrophages.

• Other laboratory tests: Serum lysozyme is elevated in 60% but is nonspecific. Chitotriosidase elevation suggests active disease. Alkaline phosphatase and transaminases may be mildly elevated if liver involvement occurs (granulomas in 50% of sarcoidosis patients at autopsy, clinical hepatic disease in 5-10%). CBC is usually normal; mild lymphocytosis or leukopenia may occur. Vitamin D level should be checked; patients with sarcoidosis and hypercalcemia require vitamin D monitoring, and supplementation is generally avoided.

• Bronchoalveolar lavage (BAL): BAL is supportive but nondiagnostic. Characteristic findings include **elevated CD4/CD8 lymphocyte ratio (typically >3.5, sometimes

First-line therapy

• Systemic glucocorticoids: oral prednisone is the ERS-endorsed initial agent for symptomatic pulmonary sarcoidosis, typically started at a moderate daily dose and tapered over months to a low maintenance dose. Steroids suppress the Th1/Th17–macrophage axis and TNF-α that sustain granulomas; they improve symptoms, radiograph, and spirometry but have not been shown to alter long-term fibrotic outcome.
• Inhaled corticosteroids: may help cough from endobronchial involvement but do not control parenchymal disease.

Escalation / steroid-sparing

• Antimetabolites: methotrexate is the preferred second-line agent (ERS 2021) when steroids fail, relapse occurs on taper, or toxicity accrues; azathioprine and mycophenolate are alternatives. Give folic acid with methotrexate.
• Anti-TNF biologics: infliximab is suggested for refractory disease, including lupus pernio and neurosarcoidosis. Screen for latent tuberculosis and endemic fungal infection before starting — TNF-α is required to keep true infectious granulomas contained.
• Antifibrotics/JAK inhibitors remain investigational for sarcoid fibrosis.

Pulmonary complications

• Progressive pulmonary fibrosis (Scadding stage 4): TGF-β–driven remodeling after repeated granuloma cycles; signals include upper-lobe traction bronchiectasis and volume loss on HRCT with falling FVC and DLCO.
• Pulmonary hypertension: multifactorial (fibrotic vascular destruction, hypoxic vasoconstriction, direct granulomatous vasculopathy, extrinsic compression by adenopathy); suspect when dyspnea and DLCO reduction are out of proportion to FVC, or with a loud P2 and right-heart failure signs.
• Mycetoma (aspergilloma) in fibrocavitary upper lobes: colonization of a healed cavity; the signal is hemoptysis in a stage 4 patient — massive hemoptysis is a medical emergency requiring airway protection and bronchial artery embolization.
• Pneumothorax from rupture of subpleural fibrotic/bullous disease: sudden pleuritic pain and dyspnea; tension physiology is an emergency.

Extrapulmonary complications

• Cardiac sarcoidosis: granulomatous infiltration of the septum and conduction system. Signals are unexplained complete heart block in a patient under 60, ventricular tachycardia, or new cardiomyopathy. Emergency — a leading cause of sarcoid death and sudden cardiac death.
• Neurosarcoidosis: basilar meningeal involvement; classic cranial nerve VII palsy, aseptic meningitis, or diabetes insipidus from hypothalamic/pituitary disease.
• Uveitis: urgent ophthalmologic referral — untreated anterior/posterior uveitis causes glaucoma, cataract, and blindness.
• Hypercalcemia/hypercalciuria: macrophage 1α-hydroxylase; presents as nephrolithiasis, nephrocalcinosis, or AKI, often worsened after sun exposure or vitamin D supplementation.

Treatment-related

• Glucocorticoids: hyperglycemia, weight gain, osteoporosis, cataracts/glaucoma, adrenal suppression on abrupt withdrawal, and infection risk.
• Methotrexate: hepatotoxicity, myelosuppression, and hypersensitivity pneumonitis — new infiltrates on therapy must be distinguished from disease flare and from infection.
• Infliximab: reactivation tuberculosis and disseminated histoplasmosis, since TNF-α maintains protective granulomas.

• The stem: young-to-middle-aged African American woman with dry cough, dyspnea, fatigue, and bilateral hilar lymphadenopathy on chest radiograph. The pathology answer is noncaseating granuloma; cytoplasmic asteroid bodies and laminated Schaumann bodies are the classic buzzwords (both nonspecific).
• Single best next step in a non-Löfgren presentation: tissue biopsy of the most accessible involved site — endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal nodes is the modern first choice per the ATS 2020 diagnosis guideline. In Löfgren syndrome (erythema nodosum + bilateral hilar adenopathy + ankle arthritis), the answer is no biopsy — observe and give NSAIDs.
• The association examiners love: hypercalcemia from macrophage 1α-hydroxylase converting 25-OH-D to calcitriol, PTH-independent. Expect suppressed PTH with a high 1,25-(OH)₂-D, hypercalciuria, and stones. Withhold vitamin D/calcium supplements.
• Do not treat stage 1 asymptomatic disease with steroids — high spontaneous remission rate. Treatment is for symptoms, functional decline, or dangerous organ involvement (ERS 2021).
• Screen every new patient for cardiac and ocular disease: baseline ECG and a slit-lamp ophthalmologic exam, because silent conduction disease and uveitis change management. Unexplained AV block in a young adult is cardiac sarcoid until proven otherwise.
• Serum ACE is a distractor: it is neither sensitive nor specific and does not establish or exclude the diagnosis; it should not be the "best test" answer.
• Anergy to tuberculin skin testing coexists with systemic Th1 activation — a negative PPD does not exclude sarcoidosis and does not exclude TB co-infection.
• Zone trap: sarcoid fibrosis is upper/mid-lobe with perilymphatic nodules; IPF is lower-lobe, subpleural honeycombing. Caseating granulomas point to TB or endemic fungi, not sarcoidosis.