David R. Moller, M.D. Johns Hopkins University Baltimore, USA Johns Hopkins CPC#4 David R. Moller, M.D. Johns Hopkins University Baltimore, USA

General Approach to Difficult to Manage Sarcoidosis Biopsy never diagnostic. Always revisit diagnosis or consider additional pathologic processes when either clinical course or clinical manifestations deviate from the expected or the typical. Consider: Not sarcoidosis Sarcoidosis plus independent process-e.g. infection, PE, CHF Sarcoidosis plus associated process- e.g. CVID, CTD, others Treatment effects Rare manifestations of sarcoidosis do occur

Asymmetric infiltrates not pulm sarc Bilateral gg-not pulm sarc with tx. Denser peripheral infiltrates, air bronchograms prob pneumonia ? More bronchiectasis, cystic lesions on L--?structural abn

Matted extensive anterior/middle mediastinal LA: very unusual distribution, asym for sarc-- ! Assume not sarcoidosis Big SVC, Big PAs, c/w pulm htn Hilar LA and central infiltrates: Narrowed, thickened bronchi

Air bronchograms No med shift,atelectasis Med-widened ?LNs only Prob RV enlargement-?cardiac sarc Cavity?

Clues from the chest CT and radiograph Possibly explained by multisystem sarcoidosis RV enlargement from pulmonary htn (?cardiac sarc) Bilateral hilar lymphadenopathy + mild ILD Bronchiectasis Not explained by pulmonary sarcoidosis: Bilat ground glass—not pulm sarcoidosis on Pred 20mg/d, ?infection ?CHF Denser L pulm infiltrate: acute/subacute pneumonia More extensive L bronciectasis/cystic changes suggest possible chronic process ?bronchial stenosis—but no atelectasis, no obstructive impairment Left sided paraaortic upper mediastinal lymphadenopathy-generalized LN: Not consistent with sarcoidosis esp with tx matted LN mass: histo,TB, other fungal >lymphoma

Differential Diagnosis of Granulomatous Lung Disease Non-infectious Infectious Sarcoidosis* Chronic beryllium disease* Hypersensitivity pneumonitis Wegener’s granulomatosis Churg-Strauss Syndrome Necrotizing sarcoid granulomatosis Lymphoma* Lung cancer, other metastatic cancer Lymphomatoid granulomatosis Crohn disease Pneumoconiosis (silicosis) Common variable immunodeficiency Blau syndrome Mycobacterial* Fungal—histo, blasto, cocci, etc* Protozoal—toxoplasmosis Spirochetal- T. pallidum Bacterial-brucella, yersinia Misc. Bronchiolitis obliterans organizing pneumonia (BOOP) Lymphocytic interstitial pneumonitis Sjogren’s syndrome *show typical compact epithelioid granulomas

What is the differential diagnosis of granulomatous inflammation in the lung in this patient? Differential diagnosis of bilateral hilar and mediastinal lymphadenopathy plus interstitial lung disease Surgical lung bx should reasonably exclude noninfectious granulomatous lung disease e.g. Wegener granulomatosis, hypersensitivity pneumonitis, cryptogenic organizing pneumonia Never can completely exclude infection e.g., mycobacterial, fungal disease or (rarely) malignancy e.g., lymphoma Look for extrapulm manifestations of sarcoidosis to confirm diagnosis

Sarcoidosis Associated Pulmonary Hypertension Pulmonary hypertension prevalence 6% unselected pulm sarcoidosis patients 50% patients with dyspnea disproportionate to PFTs 70-80% in advanced lung disease Higher when measuring exercise induced pulm htn Multiple potential mechanisms Bronchovascular distribution of inflammation Advanced fibrocystic lung disease (loss of pulmonary capillary bed) Extrinsic compression of pulmonary arteries by LN, mediastinal fibrosis Cardiac sarcoidosis with systolic, diastolic dysfunction Hypoxic vasoconstriction Primary pulmonary vascular involvement (granulomatous arteritis) Veno-occlusive disease (rare)

What is the most likely cause of her pulmonary hypertension? Common causes of pulmonary hypertension in sarcoidosis Sleep apnea (mild pulm htn) Advanced interstitial lung disease (stage 3, 4 fibrocystic sarc) Chronic pulmonary embolism (must rule out) L heart failure ( diastolic dysfunction, cardiac sarcoidosis) Pulmonary vascular sarcoidosis Interstitial lung disease does not explain pulm htn Diffusing capacity does not correlate with pulm htn DLCO decreased in pulm htn secondary to fibrocystic pulm sarcoidosis Note: these same causes may be present in infectious granulomatous diseases

Cardiac Sarcoidosis: Clinical Manifestations Common Arrhythmias Heart block/conduction defects Congestive heart failure Sudden death Rare (<10% all cardiac sarcoidosis) R ventricular involvement Valvular dysfunction Pericarditis Myocardial mass Coronary vessel involvement

What are the possible causes of the patient’s worsening shortness of breath over months and eventual demise?? Chronic slowly progressive dyspnea possibly explained by multisystem sarcoidosis with Interstitial lung disease (in part) Pulmonary hypertension- secondary pulm arterial/arteriolar involvement ? cardiac sarcoidosis Treatment unresponsiveness ? Suspect pulm htn and fibrosis Worsening dyspnea over months not explained by sarcoidosis: Left sided infiltrates/pneumonia L sided mediastinal lymphadenopathy ?new

What are the possible causes of the patient’s worsening shortness of breath over months and eventual demise? Multisystem sarcoidosis + infection pulmonary (ILD)+BHA plus L>R bronchiectasis pulmonary hypertension from pulm vascular involvement-?prox or distal arterial; possible cardiac involvement L sided infiltrates: Secondary CAP or HAP (?bronchial stenosis, rule out CVID) L mediastinal LA: ? secondary to histoplasmosis, mycobacterial, other fungal infection or nocardia which could also explain L pneumonia Infection—chronic histoplasmosis vs tuberculosis Infiltrates, mediastinal lymphadenopathy, tongue papule?, pulm htn+ from pulm artery involvement from med/hilar LN, fibrosis Lymphoma ± sarcoidosis plus infection

What are the possible causes of the patient’s worsening shortness of breath over months and eventual demise? PEA arrest Pulmonary - Respiratory arrest with hypoxia Mechanical – tension pneumothorax: fibrocystic lesions cardiac rupture with severe CHF (papillary muscles, aneursym) cardiac tamponade: pericarditis Preload and afterload changes (severe pulm htn) pulmonary embolus sepsis (pneumonia, ?mediastinitis) Metabolic changes –no evidence Note: if arrhythmia, heart block at CP arrest, suspect cardiac sarc