PANCE Blueprint Pulmonary (9%)

Patient will present as → a 38-year-old African-American woman who visits the clinic complaining of persistent dry cough, shortness of breath, and mild chest pain for the past two months. She also notes occasional fevers and unexplained weight loss. You note erythema nodosum on her lower legs. Her chest X-ray reveals bilateral hilar lymphadenopathy and reticular opacities. Pulmonary function tests show a restrictive lung disease pattern. Laboratory findings include elevated serum angiotensin-converting enzyme (ACE) levels. A biopsy of the lymph nodes obtained during bronchoscopy demonstrates noncaseating granulomas, consistent with a diagnosis of sarcoidosis.

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Sarcoidosis is a systemic granulomatous disease characterized by noncaseating (non-necrotizing) granulomas that can involve multiple organ systems

• The condition usually presents between ages 20 and 60 (more than half of cases are diagnosed after age 40; women are affected about twice as often) and is most common in Northern Europeans and African Americans
• Sarcoidosis is caused by an abnormal T-cell–mediated immune response to an unknown environmental antigen in a genetically susceptible host, leading to the formation of non-caseating granulomas
• Certain individuals appear to have a genetic predisposition, and exposure to bacterial or viral antigens, organic dusts, or inorganic particles may act as the triggering stimulus
• Clinical presentation is variable. Fever, weight loss, arthralgias, and erythema nodosum (more common in Europeans) are typical early systemic features, while cough and dyspnea may be mild or even absent despite significant pulmonary involvement
• Bilateral hilar and mediastinal lymphadenopathy on chest radiograph is the hallmark finding and is present in up to 90% of cases
• Sarcoidosis causes elevated ACE and hypercalcemia because activated macrophages within granulomas produce ACE and convert inactive vitamin D into its active form, increasing intestinal calcium absorption

"If you see hilar lymphadenopathy, it is right to think Sarcoidosis, but not always. Here is a rough guide to approaching hilar adenopathy: 

• Young female = Sarcoidosis
• Young kid with a fever, from Ohio, zookeeper =  histoplasmosis 
• Old guy in his 60's works on ceramics = Berylliosis"

Other manifestations include hepatic granulomas, granulomatous uveitis, polyarthritis, cardiac symptoms (including angina, CHF, and conduction abnormalities), cranial nerve palsies, and diabetes insipidus. Lupus pernio (violaceous plaques on the nose, cheeks, ears, and lips) is the most specific skin lesion; erythema nodosum is the most common

Blood tests may show hypercalciuria (30–50% of patients), hypercalcemia (10–20%), and an elevated serum ACE level — but ACE is not sensitive or specific enough to diagnose or rule out sarcoidosis

• ESR is often elevated
• Laboratory findings include leukopenia, hypercalcemia, hypercalciuria, and hypergammaglobulinemia (particularly in African American patients)
• Other abnormalities include elevated uric acid (not usually associated with gout), elevated alkaline phosphatase, elevated gamma-glutamyl transpeptidase, elevated levels of ACE, and pulmonary function tests showing restriction and impaired diffusing capacity
• Diagnosis = compatible clinical and imaging findings + noncaseating granulomas on biopsy + exclusion of other causes (tuberculosis, fungal infection, lymphoma)
• Biopsy the most accessible site (skin lesion, peripheral lymph node); for hilar or mediastinal nodes, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the preferred first sampling procedure (mediastinoscopy if it is nondiagnostic)
• No biopsy is needed for classic Löfgren syndrome (erythema nodosum + bilateral hilar adenopathy + fever or ankle arthritis) once infection is excluded; biopsy can often be deferred in asymptomatic bilateral hilar adenopathy with close follow-up
• FDG-PET can locate active disease and biopsy targets (gallium scanning is largely historical)
• Baseline screening for every patient: ECG (cardiac sarcoidosis), eye exam, serum calcium, creatinine, alkaline phosphatase, CBC, and PFTs with DLCO

Serial pulmonary function tests are important for assessing disease progression and guiding treatment

"Hypercalcemia in sarcoidosis is due to the uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages. 1,25-dihydroxyvitamin D3 leads to increased absorption of calcium in the intestine and to increased resorption of calcium in the bone."

Treatment for symptomatic patients consists of CORTICOSTEROIDS, methotrexate, and other immunosuppressive medications if steroid therapy is not helpful

• Many patients need no treatment — asymptomatic disease (especially stage I) often remits on its own; follow symptoms, PFTs, and imaging
• Treat when there are troublesome symptoms, declining lung function, or organ-threatening disease (heart, eyes, nervous system, hypercalcemia): oral corticosteroids (prednisone) work fastest and are the classic first-line drug; for severe or progressive disease that will need long-term treatment, methotrexate is now often preferred (alone, or with prednisone if disease is progressing rapidly) to limit steroid side effects
• Methotrexate is the main steroid-sparing agent; TNF inhibitors (infliximab) are reserved for refractory disease
• Löfgren syndrome is usually self-limited — treat with NSAIDs

The prognosis depends on the severity of the disease. Spontaneous improvement is common; however, significant disability can occur with multiorgan involvement

• Pulmonary fibrosis (with respiratory failure and pulmonary hypertension) is the leading cause of death; cardiac sarcoidosis (heart block, ventricular arrhythmias, sudden death) is the next most important