Clinicopathological Conference The Johns Hopkins Hospital

December 1, 2009

Clinical Discussant: David B. Pearse, M.D.Pulmonary and Critical Care Medicine

Timeline• March 08:

SOB, cough, pul infiltrates; Idiopathic Bronchiolitis Obliterans Organizing

Pneumonia (BOOP) Dxed• June 08:

Successfully tapered off steroids• Early December 08 to early Jan 09:

increasing SOB, cough bilat pul infiltrates, refractory hypoxemia corticosteroids, antibiotic started

Timeline• Mid Jan 09:

Sicker Lung bx: BOOP

• End Jan 09: Febrile on 100 mg/day methylprednisilone Diffuse nodular infiltrates, LLL consolidation Severe hypoxemic respiratory failure Refractory atrial arrhythmias; death

Idiopathic BOOP(or Cryptogenic Organizing Pneumonia)

• Middle aged or older; non or ex-smokers• Subacute URI presentation

Persistent cough, dyspnea, fever Patchy bilateral alveolar/interstitial infiltrates

• Path: organizing pneumonia with granulation tissue buds in alveoli and bronchioles

• No other associated diseases

Cordier JF. Cryptogenic organizing pneumonia. Clin Chest Med 25:727-738, 2004

Idiopathic BOOP• 80% steroid responsive• 1 or 2 relapses common during steroid taper

but relapses remain steroid responsive do not affect overall mortality

Cordier JF. Cryptogenic organizing pneumonia. Clin Chest Med 25:727-738, 2004

BOOP (or Organizing Pneumonia)• Bacterial infections:

Strep, Staph, Chlamydia, Legionella, Mycoplasma, Nocardia

• Viruses: HSV, HIV, Influenza, Parainfluenza, CMV

• Fungi: Cryptococcus, Pneumocystis

• Drugs/Toxins• Connective Tissue Disease• Transplantation

Cordier JF. Cryptogenic organizing pneumonia. Clin Chest Med 25:727-738, 2004

BOOP (or Organizing Pneumonia)• Bacterial infections:

Strep, Staph, Chlamydia, Legionella, Mycoplasma, Nocardia

• Viruses: HSV, HIV, Influenza, Parainfluenza, CMV

• Fungi: Cryptococcus, Pneumocystis

• Drugs• Connective Tissue Disease• Transplantation

Cordier JF. Cryptogenic organizing pneumonia. Clin Chest Med 25:727-738, 2004

Approach to Patient• Initial illness likely idiopathic BOOP

Consistent host and presentation Consistent transbronchial biopsy Complete response to steroid treatment

Approach to Patient

What was the second illness in Dec 08?

Approach to Patient

What was the second illness in Dec 08?

Assuming this was a single illness………

Second Illness: Key Findings

• Subacute presentation (2 weeks)• Corticosteroid, cephalosporin- unresponsive • Bilat upper lobe nodular interstitial onset • Progressed to alveolar-filling process • Fever despite 100 mg methylprednisilone • Lung biopsy: ?BOOP

Differential Dx of Progressive Alveolar-Filling with Respiratory Failure

• Pulmonary edema• Infection• Autoimmune• Idiopathic• Malignant

Differential Dx of Alveolar-Filling with Respiratory Failure

• Pulmonary edema• Infection• Autoimmune• Idiopathic• Malignant

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Cells

Alveolar-Filling with Subacute Respiratory Failure

• Infection• Autoimmune

Pulmonary hemorrhage syndromes• Wegener’s Granulomatosis• Microscopic polyangitis• Goodpasture’s Syndrome• Systemic Lupus Erythematosis

• Idiopathic• Malignant

Alveolar-Filling with Subacute Respiratory Failure

• Infection• Autoimmune

Pulmonary hemorrhage syndromes• Wegener’s Granulomatosis• Goodpasture’s Syndrome• Systemic Lupus Erythematosis• Microscopic polyangitis

• Idiopathic Idiopathic BOOP Eosinophilic Pneumonia Desquamative Interstitial Pneumonitis Pulmonary Alveolar Proteinosis

• Malignant

Alveolar-Filling with Subacute Respiratory Failure

• Infection• Autoimmune

Pulmonary hemorrhage syndromes• Wegener’s Granulomatosis• Goodpasture’s Syndrome• Systemic Lupus Erythematosis• Microscopic polyangitis

• Idiopathic Acute Interstitial Pneumonia (Hamman Rich) Eosinophilic pneumonia Desquamative Interstitial Pneumonitis Pulmonary alveolar proteinosis

• Malignant Alveolar cell carcinoma lymphoma

Most Likely Diagnosis: Infection• Case-specific requirements for infectious agent:

Able to infect with near-normal immunity Subacute (weeks) presentation Bilateral upper lobe interstitial/nodular infiltrates Exacerbated by steroids, progress to resp failure Unresponsive to typical broad-spectrum antibiotics Can have BOOP or BOOP-like pathology Not routinely cultured, culture difficult or takes time

Infections that Reasonably Fit• Bacteria

Nocardia asteroides*

Mycobacterium tuberculosis Nontuberculous mycobacteria

• Fungi Cryptococcus neoformans *

Histoplasma capsulatum Blastomyces dermatitis Coccidioides immitis (Pneumocystis jiroveci *)

• Virus Cytomegalovirus * *Associated with BOOP on lung biopsy

Differential Dx: My Short List1) Cryptococcus2) Nocardia3) Cytomegalovirus4) Progressive Disseminated Histoplasmosis5) Mycobacteria tuberculosis (or M. kansasii)6) (Pneumocystis)

If BOOP was present on lung biopsy:1) Cryptococcus2) Nocardia3) Cytomegalovirus

If BOOP was not present on lung biopsy:

Favor Histoplasmosis because of calcified lung nodule

Histoplasmosis

• Most common endemic mycosis in US• After inhalation, transient RES dissemination• Can see lower lobe calcified histoplasmoma• Latent infection until immunity suppressed• Upper lobe reactivation mimics TB • Exacerbated by steroids, may not see granulomas• Pericarditis and endocarditis with arrhythmiasDismukes et al. Disseminated histoplasmosis in corticosteroid-treated patients. JAMA 240: 1495-98, 1978 Kauffman C. Histoplasmosis. Clin Chest Med 30:217-25, 2009