Clinicopathological Conference   The Johns Hopkins Hospital December 1, 2009 Clinical Discussant: David B. Pearse, M.D. Pulmonary and Critical Care Medicine

Timeline March 08: June 08: Early December 08 to early Jan 09: 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: End Jan 09: Sicker Lung bx: BOOP 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 Water Pus Blood 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 List Cryptococcus Nocardia Cytomegalovirus Progressive Disseminated Histoplasmosis Mycobacteria tuberculosis (or M. kansasii) (Pneumocystis)

If BOOP was present on lung biopsy: Cryptococcus Nocardia 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 arrhythmias Dismukes et al. Disseminated histoplasmosis in corticosteroid-treated patients. JAMA 240: 1495-98, 1978 Kauffman C. Histoplasmosis. Clin Chest Med 30:217-25, 2009