Johns Hopkins CPC#4

David R. Moller, M.D.Johns Hopkins University

Baltimore, USA

• 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

General Approach to Difficult to Manage Sarcoidosis

History of Present Illness The patient is a 39 year old African American female who was diagnosed with pulmonary sarcoidosis 1.5 years prior to JHH admission after presenting with shortness of breath. At that time, radiologic studies showed parenchymal infiltrates and mediastinal adenopathy. The pathology of a lung wedge resection 1 year prior to admission was reviewed at JHH and showed granulomatous inflammation (should be good for sarc; exceptions: mycobact, fungal, rare malig). Her FVC was 70% predicted and DLCO 57% predicted. She began oral corticosteroid therapy without significant symptomatic improvement (red flag). Six months prior to admission, the patient had continued dypsnea and a transthoracic ultrasound and right heart catheterization showed the presence of pulmonary hypertension with mean PA pressure 50-55 mmHg (out of proportion to ILD/PFTs). She was started on an oral endothelin antagonist (Bosentan) which was discontinued after 5 months due no improvement in symptoms (soft flag). The patient was admitted two separate times to an outside hospital 3 and 1 month prior to JHH admission for suspected pneumonia (red flag—not pulm sarc if compliant; predisposing factors for recurrent infection—bronchial stenosis? CVID? Chronic infections eg fungal, mycobact? Alt dx: e.g. COP). At that time, during a 6 minute walk test, her SaO2 fell from 94% to 83% while inspiring 4 L/min nasal oxygen ( out of proportion to PFTs). Two days prior to JHH admission, the patient was again admitted to the critical care unit of an outside hospital for worsening shortness of breath and increased oxygen need. By report, a chest x-ray showed a bilateral lung infiltrate with the left lung being worse than the right (not pulm sarc). She was started on cefotaxime and azithromicin for bacterial pneumonia and due to a persistent pulmonary infiltrate, the patient was transferred to JHH for further evaluation and management.

Social History The patient lives at home with her husband, daughter, and son. She is a registered nurse. Prior to her decline in health, she had worked with mentally handicapped individuals. (exposure to TB, HIV, other infections) The patient has a remote smoking history of one year. She occasionally drinks alcohol. Medications (prior to presentation to outside ED) Bactrim 1 single strength/day (should be good PCP prophylaxis, esp in sarc, only on pred) Prednisone 20 mg/day (if compliant, treats pulm, most cardiac, most pulm vasc inflammation from sarcoidosis, but not fibrosis) KCl Lasix 20 mg/day Nystatin Oxygen 4 L/min Allergies No known drug allergies. Review of Systems The patient reports pink frothy sputum production, wheezing, and a 3 pillow orthopnea. The patient does not report chest pain.

Physical Exam (upon transfer) T: 36.2 C BP: 99/79 P: 94 RR: 33 SaO2: 95% on 4L NC General: NAD, obese African American female, awake and alert. HEENT: Normocephalic, atraumatic, extra-ocular movements intact, sclera anicteric,

mucosal membrane moist. A white papular lesion was present on the glossal surface. (?candida?other-TB, fungal, malig, red herring)

CV: Regular rate and rhythm. Jugular venous distension to the mid-neck while reclining at 30o. Normal S1 with a wide S2 and prominent P2. There is a 2-3/6 systolic murmur at the midsternum that is not heard at the apex or the axilla (most c/w TR, no bruit).

Lungs: No wheezes, crackles, or rhonci. (typical for sarcoidosis, equal breath sounds?) Abdomen: Soft, nontender, nondistended, positive bowel sounds. Extremities: No clubbing, cyanosis, or edema,, capillary refill <2s, 2+ pulses throughout.

Neuro: Alert and oriented x 3, cranial nerves II-XII intact, sensation intact to fine touch, normal muscle bulk and tone, coordination grossly normal.

Laboratory Values (upon transfer) Na 134; K 4.5; Cl 101; HCO3 18 (suggests no chronic hypercapnia); BUN 20; Cr 1.0;

Glucose 159; Calcium 7.6 WBC 12.6;Hct 34.8%; Platelet 233k;

Pulmonary Function Tests (outside hospital 1 month prior to admission) FEV1/FVC 85%, FVC 60% predicted, DLCO 53% predicted (mod restriction, modsevere reduction in diffusing capacity: worse— and does not explain degree of 02 desaturation, pulm htn)

? More bronchiectasis, cystic lesions on L--?structural abn

Asymmetric infiltrates not pulm sarc

Denser peripheral infiltrates, air bronchograms prob pneumonia

Bilateral gg-not pulm sarc with tx.

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 Differential Diagnosis of Granulomatous Lung DiseaseGranulomatous Lung Disease

• 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

Non-infectious Infectious

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